WO2025034549A1

WO2025034549A1 - Compositions and methods for treating cardiometabolic inflammation and atherosclerosis

Info

Publication number: WO2025034549A1
Application number: PCT/US2024/040700
Authority: WO
Inventors: Robert L. RAFFAI; Tuan Anh PHU; Martin Ng; Ngan K. VU; Alex GAO
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-08-04
Filing date: 2024-08-02
Publication date: 2025-02-13
Anticipated expiration: 2026-02-04

Abstract

Disclosed are methods of reducing cardiometabolic inflammation, treating or preventing atherosclerosis, and treating, preventing, or reducing cardiac failure in subjects with hyperlipidemia type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease using compositions comprising miR-146 agonists or mimics, miR-142 antagonists, or combinations thereof. Also disclosed herein are methods of treating or suppressing inflammation caused by hyperlipidemia, increasing plasma IL-10 levels, enhancing fatty acid oxidation and oxidative phosphorylation, decreasing hematopoiesis, decreasing myelopoiesis, decreasing aortic leukocyte accumulation, and suppressing glycolysis and oxidative stress in immune cells in subjects in need thereof by administering miR-146 agonists or mimics, miR-142 antagonists, or combinations thereof.

Description

COMPOSITIONS AND METHODS FOR TREATING CARDIOMETABOLIC INFLAMMATION AND ATHEROSCLEROSIS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No. 63/517,810, filed on Augugt 4, 2023. The content of this earlier filed application is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant Number P30 DK063720 awarded by the National Institutes of Health. The government has certain rights in this invention. REFERENCE TO A SEQUENCE LISTING The present application contains a Sequence Listing that is submitted concurrent with the filing of this application in XML format, containing the file name “37759_0584P1_SL.xml,” created on August 1, 2024, and having a size of 8,192 bytes. The Sequence Listing is hereby incorporated by reference pursuant into the present application in its entirety. BACKGROUND Cardiometabolic inflammatory disease and its associated complications are leading causes of morbidity and mortality due to the increasing prevalence of diabetes. Risk factors contributing to its pathogenesis include obesity, insulin-resistance, dyslipidemia, and hypertension. Recent findings point to chronic, unresolved inflammation as a major contributor to the onset and progression of cardiometabolic disease and its complications. To fully treat the cardiometabolic inflammation, effective treatments and new targets are needed. BRIEF SUMMARY Disclosed are methods of reducing cardiometabolic inflammation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or preventing atherosclerosis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating systemic inflammation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating, preventing, or reducing cardiac failure in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating, preventing, or reducing cardiac failure in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or suppressing systemic and tissue inflammation caused by hyperlipidemia in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or suppressing systemic and tissue inflammation caused by hyperlipidemia in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of increasing plasma IL-10 levels in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of increasing plasma IL-10 levels in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of enhancing fatty acid oxidation and oxidative phosphorylation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of enhancing fatty acid oxidation and oxidative phosphorylation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of enhancing fatty acid oxidation and/or oxidative phosphorylation in one or more immune cells, hematopoietic stem cells, or progenitor cells, the methods comprising administering to a subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of enhancing fatty acid oxidation and/or oxidative phosphorylation in one or more immune cells, hematopoietic stem cells, or progenitor cells, the methods comprising administering to a subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing hematopoiesis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing hematopoiesis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing myelopoiesis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing myelopoiesis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing aortic leukocyte accumulation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing aortic leukocyte accumulation in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of suppressing glycolysis and oxidative stress in immune cells, the methods comprising administering to a subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of suppressing glycolysis and oxidative stress in immune cells, the methods comprising administering to a subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing inflammatory cytokines in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of decreasing inflammatory cytokines in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR- 146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or ameliorating a symptom of a cardiometabolic disease in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or ameliorating a symptom of a cardiometabolic disease in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or ameliorating a symptom of a chronic inflammatory disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of treating or ameliorating a symptom of a chronic inflammatory disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of ameliorating a symptom of atherosclerosis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of ameliorating a symptom of atherosclerosis in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of enhancing oxidative phosphorylation in a cell of a subject in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein are methods of enhancing oxidative phosphorylation in a cell of a subject in a subject, the methods comprising administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Additional advantages of the disclosed method and compositions will be set forth in part in the description which follows, and in part will be understood from the description, or may be learned by practice of the disclosed method and compositions. The advantages of the disclosed method and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed method and compositions and together with the description, serve to explain the principles of the disclosed method and compositions. FIGS.1A-1N show that ApoE suppresses NF-κB-driven glycolysis and glucose uptake in myeloid cells via the upregulation of miR-146a. FIG.1A is a graph showing representative Seahorse Glycolytic Rate Assay using quantified cell-normalized glycolysis-associated proton efflux rate (glycoPER). GlycoPER is calculated by taking the difference between total PER and mitochondrial PER. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2-Deoxy-D-glucose (50 mM). FIG.1B is a graph showing Basal Glycolysis, % PER from Glycolysis, and Compensatory Glycolysis as measured and calculated from the Seahorse Glycolytic Assay. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. Two independent replicates are shown; n = 10 total per group. FIGS.1C-D show qRT-PCR analysis of miR-146a-5p expression in Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDM/BMDC (FIG.1C) or non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector (FIG. 1D). One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.1E-F show qRT-PCR analysis of Slc2a1 mRNA expression (FIG.1E) and 2- deoxy-D-Glucose-6-phosphate (2-DG6P) uptake (FIG.1F) in Apoe^-/- BMDM pre-treated with BAY11-7085 (an NF-kB inhibitor) prior to stimulation with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 1G show qRT-PCR analysis of Slc2a1 mRNA expression in Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDM/BMDC cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG. 1H depicts graphs showing percentage of GLUT1⁺ cells and medium fluorescent intensity (MFI) of GLUT1 in Apoe^-/- vs. Apoe^+/+ BMDM stimulated with LPS (100 ng/mL) for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.1I show 2-deoxy-D-Glucose-6-phosphate (2-DG6P) uptake assay in Apoe^-/- vs. Apoe^+/+ BMDM cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.1J show lactate accumulation in conditioned media by Apoe^-/- vs. Apoe^+/+ BMDM cultured in basal or LPS- stimulated condition (100 ng/mL) for 18 hours as measured by the L-Lactate Assay Kit. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 1K shows qRT-PCR analysis of Slc2a1 mRNA expression in non-transfected Apoe^-/- BMDM vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector cultured in basal or LPS- stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.1L depicts graphs showing percentage of GLUT1⁺ cells and medium fluorescent intensity (MFI) of GLUT1 measured by flow cytometry in non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 1M shows 2-deoxy-D-Glucose-6-phosphate (2-DG6P) uptake assay in non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.1N shows lactate accumulation in conditioned media by non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector cultured in basal or LPS- stimulated condition (100 ng/mL) for 18 hours as measured by the L-Lactate Assay Kit. One representative experiment out of two independent replicates is shown; n = 4-5 per group. qRT- PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test, one-way ANOVA followed by Holm-Sidak post-test, or two-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.2A-3M show that ApoE enhances fatty acid oxidation and oxidative phosphorylation via a miR-142a/CPT1A axis. FIG.2A is a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.2B is a graph showing quantified cell-normalized mitochondrial OCR. Two independent replicates are shown; n = 10 total per group. FIG.2C is a graph showing MFI of Tetramethylrhodamine (TMRM) staining measured by flow cytometry in Apoe^-/- vs. Apoe^+/+ BMDM/BMDC. One representative experiment out of two independent replicates is shown; n = 5 per group. FIGS.2D-E show qRT-PCR analysis of miR-142a-3p expression in Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDM /BMDC (FIG.2D) or non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector (FIG. 2E). One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.2F show qRT-PCR analysis of Cpt1a mRNA expression in Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDM cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS. 2G-H show Western blot analysis (FIG.2G) and quantification (FIG.2H) of CPT1A protein levels in cell lysates of Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDM. Two independent replicates are shown; n = 8 total per group. FIGS.2I-J show Western blot analysis (FIG.2I) and quantification (FIG.2J) of CPT1A protein levels in cell lysates of non-transfected Apoe^-/- BMDM vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector. Two independent replicates are shown; n = 6 total per group. FIG.2K show qRT-PCR analysis of Cpt1a mRNA expression in non-transfected Apoe^-/- BMDM vs. cells transfected with 12.5 pmol of miR-142 inhibitor or negative control cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4 per group. FIGS. 2L-M show Western blot analysis (FIG.2L) and quantification (FIG.2M) of CPT1A protein levels in cell lysates of non-transfected Apoe^-/- BMDM vs. cells transfected with 12.5 pmol of miR-142 inhibitor or negative control. Two independent replicates are shown; n = 8 total per group. FIG.2N is a graph showing representative OCR measurement in response to etomoxir treatment as measured by the Agilent Seahorse instrument. Etomoxir (4 µM) and O, oligomycin (1 µM). FIG.2O is a graph showing quantified cell-normalized mitochondrial OCR drop upon CPT1a inhibition by etomoxir. Two independent replicates are shown; n = 9 total per group. FIG.2P is a graph showing MFI of Tetramethylrhodamine (TMRM) staining measured by flow cytometry in non-transfected Apoe^-/- BMDM vs. cells transfected with 12.5 pmol of miR-142 inhibitor or negative control. One representative experiment out of two independent replicates is shown; n = 5 per group. FIG.2Q shows metabolomic analysis of cell extracts from Apoe^-/- vs. Apoe^+/+ BMDM (n = 4 per group, p < 0.05). qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. Western blot data was quantified using ImageJ and data was normalized to GAPDH levels. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t- test, one-way ANOVA followed by Holm-Sidak post-test, or two-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.3A-3Q show that ApoE suppresses inflammation through control of microRNA signaling axes and bioenergetic metabolism in myeloid cells of hyperlipidemic mice. FIG.3A shows qRT-PCR analysis of miR-146a-5p and miR-142a-3p expression in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.3B shows qRT-PCR analysis of Slc2a1 mRNA expression in cultured in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.3C is a graph showing MFI of GLUT1 in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.3D shows 2-deoxy-D-Glucose-6-phosphate (2-DG6P) uptake assay in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.3E shows lactate accumulation in conditioned media by Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours as measured by the L-Lactate Assay Kit. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.3F shows 2-deoxy-D-Glucose- 6-phosphate (2-DG6P) uptake in Apoe^-/- Ldlr^-/- peritoneal macrophages pre-treated with BAY11- 7085 before being stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.3G shows qRT-PCR analysis of Cpt1a mRNA expression in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.3H-I show Western blot analysis (FIG.3I) and quantification (FIG.3J) of CPT1A protein levels in cell lysates of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages. Two independent replicates are shown; n = 8 total per group. FIG.3J is a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.3K is a graph showing quantified cell-normalized mitochondrial OCR. Two independent replicates are shown; n = 10 total per group. FIG.3L is a graph showing MFI quantification of Tetramethylrhodamine (TMRM) staining by flow cytometry in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.3M is a graph showing representative OCR measurement in response to etomoxir treatment as measured by the Agilent Seahorse instrument. Etomoxir (4 µM) and O, oligomycin (1 µM). FIG.3N is a graph showing quantified cell-normalized mitochondrial OCR drop upon CPT1a inhibition by etomoxir. Two independent replicates are shown; n = 10 total per group. FIG.3O is a graph showing representative Seahorse Glycolytic Rate Assay using quantified cell-normalized glycolysis-associated proton efflux rate (glycoPER). glycoPER is calculated by taking the difference between total PER and mitochondrial PER. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2-Deoxy-D-glucose (50 mM). FIG.3P is a graph showing Basal Glycolysis, % PER from Glycolysis, and Compensatory Glycolysis as measured and calculated from the Seahorse Glycolytic Assay. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. Two independent replicates are shown; n = 10 total per group. FIG.3Q is a multiplex immunoassay analysis of TNF-α, IL-6, and IL-1β cytokines released by Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- splenic cells, bone marrow cells, and BMDM upon LPS stimulation (100 ng/mL) for 18 hours. Data are displayed as log2 fold- change relative to Apoe^h/h Ldlr^-/- cells. One representative experiment out of two independent replicates is shown; n = 4 per group. FIG.3R shows qRT-PCR analysis of H2-Ab1, Cd86, Cd80, Tnf, Il1b, Mcp1, Il6, Arg1, Retnla, and Chil3 mRNA expression in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr- ^/- peritoneal macrophages. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.3S shows MFI of MHC-II, CD86, and CD80 expression in total DC, cDC1, cDC2, and plasmacytoid DC measured by flow cytometry. qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. Western blot data was quantified using ImageJ and data was normalized to GAPDH levels. The data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test or one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.4A-4Q show that ApoE suppresses hyperlipidemia-driven hematopoiesis and myelopoiesis by enhancing FAO and OxPHOS while suppressing glycolysis in HSPC. FIGS. 4A-B show qRT-PCR analysis of miR-146a-5p and miR-142a-3p (FIG.4A) and Slc2a1 and Cpt1a (FIG.4B) expression in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- LK cells. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.4C show 2-DG uptake assay in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- bone marrow and splenic cells. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIGS. 4D-E show 2-NBDG uptake (FIG.4D) and GLUT1 expression (FIG.4E) in Lin⁺, Lin-, LK, Lin- c-Kit⁺ Sca-1⁺ (LSK), CD34⁺ LSK, and CD34- LSK cells from Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice measured by flow cytometry. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.4F is a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.4G is a graph showing quantified cell-normalized mitochondrial OCR. Two independent replicates are shown; n = 10 total per group. FIG.4H is a graph showing representative OCR measurement in response to etomoxir treatment as measured by the Agilent Seahorse instrument. Etomoxir (4 µM) and O, oligomycin (1 µM). FIG.4I is a graph showing quantified cell-normalized mitochondrial OCR drop upon CPT1a inhibition by etomoxir. Two independent replicates are shown; n = 10 total per group. FIG.4J is a graph showing representative Seahorse Glycolytic Rate Assay using quantified cell-normalized glycolysis- associated proton efflux rate (glycoPER). glycoPER is calculated by taking the difference between total PER and mitochondrial PER. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2- Deoxy-D-glucose (50 mM). FIG.4K is a graph showing Basal Glycolysis, % PER from Glycolysis, and Compensatory Glycolysis as measured and calculated from the Seahorse Glycolytic Assay. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. Two independent replicates are shown; n = 10 total per group. FIG.4L shows representative plots of flow cytometric analyses of hematopoietic stem and progenitor cells in the spleen. FIG.4M depicts graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the bone marrow of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.4N-O show representative flow cytometric analyses of circulating myeloid cells (FIG.4N) and measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the circulation of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice (FIG.4O). One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.4P-Q show representative flow cytometric analyses of splenic myeloid cells (FIG.4P) and quantification of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the spleen of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice (FIG.4Q). One representative experiment out of three independent replicates is shown; n = 4-5 per group. qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. The data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using unpaired two-tailed Student’s t-test. Data are presented as mean ± SEM. FIGS.5A-5O show that cell-intrinsic ApoE suppresses hyperlipidemia-driven inflammation, hematopoiesis, and myelopoiesis in hyperlipidemic mice by regulating the miR- 146a/NF-κB/GLUT1 and miR-142a/CPT1A signaling axes. FIG.5A is a schematic of reciprocal transplantation of five-week-old donor apoE-expressing or apoE-deficient BM cells to HFD-fed five-week-old recipient AAV8-PCSK9 Apoe^+/+ CD45.1 mice or HFD-fed Apoe^-/- CD45.2 mice. Bone marrow depletion in recipient mice was done by injecting 20 mg/kg of busulfan for five days (Peake K, et al. J Vis Exp.201598):e52553). FIG.5B is a flow cytometric plot showing reconstitution of donor BM cells in recipient mice. FIGS.5C-D show Cholesterol measurements in FPLC fractions from collected plasma (FIG.5C) and plasma total cholesterol and triglycerides (FIG.5D) in HFD-fed 11-week-old BMT mice. FIGS.5E-I show qRT-PCR analysis of Apoe (FIG.5E), miR-146a-5p (FIG.5F), miR-142a-3p (FIG.5G), Slc2a1 (FIG.5H), and Cpt1a (FIG.5I) levels in circulating Ly6C^hi monocytes of HFD-fed 11-week-old BMT mice. FIG.5J shows qRT-PCR analysis of Tnf, Il1b, Mcp1, Il6, & Il10 mRNA levels in circulating Ly6C^hi monocytes of HFD-fed 11-week-old BMT mice. FIG.5K shows multiplex immunoassay analysis of IFN-γ, TNF-α, IL-6, IL-1β, & IL-10 cytokines in plasma of HFD-fed 11-week-old BMT mice. FIGS.5L-M depicts graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the bone marrows (FIG.5L) and spleens (FIG.5M) of HFD-fed 11-week-old BMT mice. FIG.5N show measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the circulation of HFD-fed 11-week-old BMT mice. FIG.5O show measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the spleen of HFD-fed 11-week-old BMT mice. qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. The data are taken from HFD-fed 11-week-old Apoe^+/+ CD45.1 AAV8-PCSK9-injected or Apoe^-/- CD45.2 mice that received reciprocal BMT and pooled from two independent experiments; n = 7 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.6A-6G show that systemic delivery of miR-146a mimics or miR-142a antagonists suppresses inflammation through control of microRNA signaling axes and bioenergetic metabolism in myeloid cells of hyperlipidemic mice. FIG.6A is a schematic diagram depicting the injections of RNA oligonucleotides in HFD-fed AAV8-PCSK9 mice. FIG.6B is a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.6C is a graph showing quantified cell- normalized mitochondrial OCR. FIG.6D is a graph showing representative Seahorse Glycolytic Rate Assay using quantified cell-normalized glycolysis-associated proton efflux rate (glycoPER). glycoPER is calculated by taking the difference between total PER and mitochondrial PER. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2-Deoxy-D-glucose (50 mM). FIG.6E is a graph showing Basal Glycolysis, % PER from Glycolysis, and Compensatory Glycolysis as measured and calculated from the Seahorse Glycolytic Assay. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. FIG.6F shows a multiplex immunoassay analysis of IFN-γ, TNF-α, IL-6, IL-1β, & IL-10 cytokines in plasma of HFD-fed 12-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.6G shows qRT-PCR analysis of Tnf, Il1b, Mcp1, Il6, Il10, Arg1, Retnla, & Chil3 mRNA levels in splenic F4/80⁺ macrophages of HFD-fed 12-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. The data from FIGS.4I-J are taken from HFD-fed 12-week-old AAV8-PCSK9 mice and pooled from two independent experiments; n = 8-10 per group. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.7A-7J show that systemic delivery of miR-146a mimics or miR-142a antagonists suppresses hematopoiesis and myelopoiesis through control of microRNA signaling axes and bioenergetic metabolism in HSPC of hyperlipidemic mice. FIG.7A shows qRT-PCR analysis of miR-146a-5p and miR-142a-3p levels in LK cells of HFD-fed 12-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.7B shows qRT- PCR analysis of Slc2a1 and Cpt1a mRNA levels in LK cells of HFD-fed 12-week-old AAV8- PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.7C is a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.7D is a graph showing quantified cell- normalized mitochondrial OCR. FIG.7E is a graph showing representative Seahorse Glycolytic Rate Assay using quantified cell-normalized glycolysis-associated proton efflux rate (glycoPER). glycoPER is calculated by taking the difference between total PER and mitochondrial PER. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2-Deoxy-D-glucose (50 mM). FIG.7F is a graph showing Basal Glycolysis, % PER from Glycolysis, and Compensatory Glycolysis as measured and calculated from the Seahorse Glycolytic Assay. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. FIGS.7G-H depicts graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the bone marrows (FIG.7G) and spleens (FIG.7H) of HFD-fed 12-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.7I shows measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the spleen of HFD-fed 12-week-old AAV8- PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.7J shows measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the circulation of HFD-fed 12-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. The data from FIGS.4I-J are taken from HFD- fed 12-week-old AAV8-PCSK9 mice and pooled from two independent experiments; n = 8-10 per group. qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR- 16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.8A-8K show that ApoE suppresses glucose uptake in cultured myeloid cells by downregulating NF-kB activity via miR-146a, related to FIG.1. FIG.8A shows qRT-PCR analysis of Apoe mRNA expression in Wildtype BMDM, peritoneal macrophages, splenic CD11c⁺ cells, immature BMDC (iBMDC), mature BMDC (mBMDC), splenic CD4⁺ cells, and splenic CD8⁺ cells. One representative experiment out of two independent replicates is shown; n = 4 per group. FIG.8B shows qRT-PCR analysis of Apoe mRNA expression in Apoe^+/+ BMDM/BMDC, non-transfected Apoe^-/- BMDM/BMDC, Apoe^-/- cells transfected with an empty vector, or Apoe^-/- cells transfected with 100 ng/mL of ApoE expressing vector. One representative experiment out of three independent replicates is shown; n = 4 per group. FIG.8C shows a Western blot for ApoE protein in cell lysates of Apoe^+/+ (wildtype) BMDM/BMDC, non-transfected Apoe^-/- BMDM/BMDC, Apoe^-/- cells transfected with an empty vector, or Apoe^-/- cells transfected with 100 ng/mL of ApoE expressing vector. One representative experiment out of two independent replicates is shown. FIG.8D shows qRT-PCR analysis of Irak1 and Traf6 mRNA levels in Apoe^-/- vs. Apoe^+/+ BMDM/BMDC stimulated with 100 ng/mL LPS for 0, 4, and 18 hrs. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.8E shows qRT-PCR analysis of Irak1 and Traf6 mRNA levels in non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL ApoE expressing or empty vector cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.8F shows MFI of nuclear NF-kB phospho-p65 subunit measured by flow cytometry in Apoe^+/+ (wildtype) BMDM, non-transfected Apoe^-/- BMDM, Apoe^-/- BMDM transfected with an empty vector, or Apoe^-/- BMDM transfected with 100 ng/mL of ApoE expressing vector in basal condition or stimulated with 100 ng/mL LPS for 4 hrs. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.8G shows qRT-PCR analysis of Irak1 and Traf6 mRNA levels in non-transfected Apoe^+/+ BMDM/BMDC vs. cells transfected with 12.5 pmol of miR-146a inhibitor or negative control upon LPS stimulation (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG. 8H shows qRT-PCR analysis of Slc2a1 mRNA levels in non-transfected Apoe^+/+ BMDM vs. cells transfected with 12.5 pmol of miR-146a inhibitor or negative control in basal or LPS- stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.8I depicts graphs showing percentage of GLUT1⁺ cells and medium fluorescent intensity (MFI) of GLUT1 measured by flow cytometry in non-transfected Apoe^+/+ BMDM vs. cells transfected with 12.5 pmol of miR-146a inhibitor or negative control stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.8J shows 2- DG6P uptake assay in non-transfected Apoe^+/+ BMDM vs. cells transfected with 12.5 pmol of miR-146a inhibitor or negative control cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.8K shows lactate accumulation in conditioned media by non-transfected Apoe^+/+ BMDM vs. cells transfected with 12.5 pmol of miR-146a inhibitor or negative control cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours as measured by the L- Lactate Assay Kit. One representative experiment out of two independent replicates is shown; n = 4-5 per group. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either the one-way ANOVA followed by Holm-Sidak post-test or two-way ANOVA followed by Holm-Sidak post- test. Data are presented as mean ± SEM. FIGS.9A-9B show that ApoE enhances mitochondrial membrane potential by controlling microRNA expression in cultured myeloid cells, related to FIG.2. FIG.9A is a graph showing MFI of Tetramethylrhodamine (TMRM) staining measured by flow cytometry in non-transfected Apoe-/- BMDM/BMDC vs. cells transfected with 100 ng/mL ApoE expressing or empty vector. One representative experiment out of three independent replicates is shown; n = 5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using the one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIG. 9B shows a heatmap showing the distinct microRNA expression profiles between Apoe-/- (EKO) and Apoe+/+ (WT) BMDM (n = 3 per group, p <0.05). FIGS.10A-10I show that ApoE enhances fatty acid oxidation and reduces neutral lipid accumulation in cultured myeloid cells, related to FIG.2. FIG.10A shows qRT-PCR analysis of Cpt1a mRNA expression in Apoe^-/-, Apoe^+/-, or Apoe^+/+ BMDC cultured in basal or LPS- stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.10B-C show Western blot analysis (FIG.10B) and quantification (FIG.10C) of CPT1A protein levels in cell lysates of non- transfected Apoe^-/- BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector. Two independent replicates are shown; n = 6 per group. FIG.10D shows qRT-PCR analysis of Cpt1a mRNA expression in Apoe^+/+ BMDC/BMDM, non-transfected Apoe^-/- BMDC/BMDM, Apoe^-/- BMDC/BMDM transfected with an empty vector, or Apoe^-/- BMDC/BMDM transfected with 100 ng/mL of ApoE expressing vector cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.10E shows qRT-PCR analysis of Cpt1a mRNA expression in THP-1 macrophages transfected with 12.5 pmol of miR-142 inhibitor or negative control; one replicate is shown, n = 5. FIG.10F shows Western blot analysis of CPT1A protein levels in cell lysates of THP-1 macrophages transfected with 12.5 pmol of miR-142 inhibitor or negative control; one replicate is shown. FIG.10G is a graph showing MFI of LipidTOX staining measured by flow cytometry in Apoe^+/+ vs. Apoe^-/- BMDM/BMDC. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 10H is a graph showing MFI of LipidTOX staining measured by flow cytometry in non- transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL ApoE expressing or empty vector. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.10I is a graph showing MFI of LipidTOX staining measured by flow cytometry in non-transfected Apoe^-/- BMDM vs. cells transfected with 12.5 pmol of miR-142 inhibitor or negative control. One representative experiment out of two independent replicates is shown; n = 4-5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test or one-way ANOVA followed by Holm-Sidak post- test. Data are presented as mean ± SEM. FIG.11 shows altered metabolite levels in M0 vs. M2 macrophages, related to FIG.2. Metabolomic analysis of cell extracts from naïve (Ctrl) or IL-4-polarized (IL-4) BMDM (n = 4 per group, p < 0.05). FIGS.12A-12F show metabolic parameters of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice, related to FIG.3. FIGS.12A-B show Western blot analysis of BMDM vs. peritoneal macrophage endogenous ApoE (FIG.12A) and plasma ApoE ((FIG.12B). One representative experiment of two independent replicates is shown. FIGS.12C-F show body weights ((FIG. 12C), plasma total cholesterol ((FIG.12D), and triglycerides ((FIG.12E), and cholesterol measurements in FPLC fractions from collected plasma ((FIG.12F) of 14-week-old Apoe^-/- Ldlr- ^/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test or one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.13A-13M show that ApoE suppresses NF-kB-driven glucose uptake and enhances CPT1A-driven FAO in peritoneal macrophages from hyperlipidemic mice, related to FIG.3. FIG.13A shows qRT-PCR analysis of miR-146a-5p and miR-142a-3p expression in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- splenic CD11c⁺ cells. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIGS.13B-C show qRT-PCR analysis of Irak1 and Traf6 mRNA levels in peritoneal macrophages (FIG.13B) and CD11c⁺ cells (FIG. 13C) of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.13D shows MFI of nuclear NF-κB phospho-p65 subunit measured by flow cytometry in peritoneal macrophages, splenic dendritic cells (Ly6C- MHCII⁺ CD11c⁺ cells), and blood monocytes (CD45⁺ CD11b⁺ CD115⁺ cells) of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice upon LPS stimulation (100 ng/mL) for 4 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 13E shows qRT-PCR analysis of Slc2a1 mRNA levels in CD11c⁺ cells of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG. 13F depicts a histogram and a graph showing percentage of GLUT1⁺ cells and MFI of GLUT1 in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.13G shows qRT-PCR analysis of Slc2a1 mRNA expression in Apoe-/- Ldlr-/- peritoneal macrophages pre-treated with BAY11-7085 before being stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG.13H shows qRT-PCR analysis of Cpt1a mRNA levels in CD11c⁺ cells of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice cultured in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4- 5 per group. FIGS.13I-J shows Western blot analysis (FIG.13I) and quantification (FIG.13J) of CPT1A protein levels in cell lysates of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- CD11c⁺ cells. Two independent replicates are shown; n = 8 total per group. FIG.13K shows a representative flow cytometric histogram of Tetramethylrhodamine (TMRM) staining in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages. FIG.13L shows a graph showing MFI of Tetramethylrhodamine (TMRM) staining by flow cytometry in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- CD11c⁺ cells. One representative experiment out of two independent replicates is shown; n = 4-5 per group. FIG. 13M shows a graph showing MFI of LipidTOX staining measured by flow cytometry in Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- peritoneal macrophages and CD11c⁺ cells. One representative experiment out of two independent replicates is shown; n = 4-5 per group. The data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t- test, one- or two-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.14A-14H show that ApoE suppresses the capacity for antigen presentation, co- stimulation, and inflammatory cytokine production in myeloid cells in vivo and in vitro, related to FIG.3. FIG.14A shows representative flow cytometric analyses of dendritic cell subsets in the spleen of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. FIG.14B shows the total number of total DC (Ly6C- MHCII⁺ CD11c⁺), cDC1 (Ly6C- MHCII⁺ CD11c⁺ B220- CD11b- CD8a⁺), cDC2 (Ly6C- MHCII⁺ CD11c⁺ B220- CD11b⁺ CD8a-), and plasmacytoid DC (Ly6C- MHCII⁺ CD11c⁺ B220⁺) normalized by spleen weight. One representative experiment out of three independent replicates is shown; n = 3-5 per group. FIG.14C shows a representative histogram displaying MFI of MHC-II, CD86, and CD80 expression in total DC, cDC1, cDC2, and plasmacytoid DC measured by flow cytometry. FIG.14D shows the qRT-PCR analysis of H2-Ab, Cd86, Cd80, Il12, Tnfa, Il6, and Il1b mRNA expression in splenic CD11c⁺ cells of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. Data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG. 14E shows the MFI of MHCII, CD86, and CD80 expression in Apoe^+/+ vs. Apoe^-/- BMDC stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.14F shows the qRT-PCR analysis of H2-Ab, Cd86, Cd80, Il12, Tnfa, Il6, and Il1b mRNA expression in Apoe^+/+ vs. Apoe^-/- BMDC stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.14G shows the qRT-PCR analysis of Cd86, Cd80, Tnfa, Il6, Il1b, and Mcp1 mRNA expression in Apoe^+/+ vs. Apoe^-/- BMDM stimulated with 100 ng/mL LPS for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.14H shows the qRT-PCR analysis of H2-Ab1, Cd86, Cd80, Tnfa, Il1b, Mcp1, and Il6 mRNA expression in non-transfected Apoe^-/- BMDM/BMDC vs. cells transfected with 100 ng/mL of ApoE expressing or empty vector upon LPS stimulation (100 ng/mL) for 18 hours. One representative experiment out of three independent replicates is shown; n = 4-5 per group. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. The data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test or one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.15A-15F show that ApoE suppresses hematopoiesis and GLUT1-mediated glucose uptake in HSPC of hyperlipidemic mice, related to FIG.4. FIGS.15A-B shows representative histograms displaying 2-NBDG uptake (A) and GLUT1 expression (B) in Lin⁺, Lin-, LK, Lin- c-Kit⁺ Sca-1⁺ (LSK), CD34⁺ LSK, and CD34- LSK cells from Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice measured by flow cytometry. FIG.15C shows a representative image of spleens isolated from Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. FIGS.15D-E show spleen weight normalized by total body weight (FIG.15D) and total splenocytes count normalized by spleen weight (FIG.15E) of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. FIG.15F depicts graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the spleen of Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. One representative experiment out of three independent replicates is shown; n = 4-5 per group. qRT- PCR results for mRNA expression were normalized to B2m or Gapdh. The data are taken from chow-fed 12 to 14-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using either unpaired two-tailed Student’s t-test or one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.16A-16E show that systemic infusions of miR-146a mimics or miR-142a inhibitors controlled Slc2a1 and Cpt1a mRNA expression in splenic macrophages of hyperlipidemic mice, related to FIG.6. FIGS.16A-C show plasma total cholesterol (FIG.16A), triglycerides (FIG.16B) and cholesterol measurements in FPLC fractions from collected plasma (FIG.16C) of HFD-fed nine-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.16D show qRT-PCR analysis of miR- 146a-5p and miR-142a-3p levels in splenic F4/80⁺ macrophages of HFD-fed nine-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. FIG.16E show qRT-PCR analysis of Slc2a1 and Cpt1a mRNA levels in splenic F4/80⁺ macrophages of HFD-fed nine-week-old AAV8-PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. qRT-PCR results for microRNA expression were normalized to U6 snRNA and miR-16-5p expression, with UniSp6 used as a spike-in control. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. Data are taken from HFD-fed 12-week-old AAV8-PCSK9 mice. The data above are pooled from two independent experiments; n = 8-10 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.17A-17C show that delivery of miR-146a mimics or miR-142a inhibitors suppressed LPS-driven pro-inflammatory response while promoting IL-4-driven anti- inflammatory response in cultured macrophages, related to FIG.6. FIG.17A shows qRT-PCR analysis of Tnfa, Il1b, Mcp1, and Il6 mRNA expression in non-transfected Apoe^-/- BMDM vs. cells transfected with 12.5 pmol of miR-142 inhibitor or negative control upon LPS stimulation (100 ng/mL) for 18 hours. FIG.17B shows qRT-PCR analysis of Tnfa, Il6, Il1b, and Mcp1 mRNA levels in non-transfected Apoe^+/+ BMDM vs. cells transfected with 12.5 pmol of miR- 146a inhibitor or negative control in basal or LPS-stimulated condition (100 ng/mL) for 18 hours. FIG.17C shows qRT-PCR analysis of Tnfa, Mcp1, and Il6 mRNA expression in THP-1 macrophages treated with 100 ng/mL LPS for 18 hours and Arg1, Retnla, and Chil3 mRNA expression in THP-1 macrophages treated with 20 ng/mL murine IL-4; one replicate is shown, n = 5. qRT-PCR results for mRNA expression were normalized to B2m or Gapdh. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.18A-18H show that ApoE suppresses atherosclerosis and lesion instability in hyperlipidemic mice. FIGS.18A-B show representative flow cytometry plots of leukocyte subsets from aorta (FIG.18A) and quantification of aortic CD45⁺ cells, macrophages, CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes (FIG.18B). FIGS.18C-D show Histological analysis of oil red O (ORO) staining (FIG.18C) and quantification of cross sections of aortic sinus positive for ORO (Minhas PS, et al. Nat Immunol.2019;20(1):50-63) (FIG.18D) from Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. FIG.18E show a representative cross-sectional view of aortic root stained with Hoechst and anti-MOMA-2 to measure necrosis area from Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. Necrosis area is defined as Hoechst-negative and MOMA2- negative region. Dashed lines show the boundary of the developing necrotic core. FIG.18F show the quantification of necrotic core area as a percentage of total plaque area. FIGS.18G-H show representative images (FIG.18G) and (FIG.18H) quantification of MOMA-2⁺ macrophages in the atherosclerotic plaques of aortic root areas. Data are taken from chow-fed 30-week-old Apoe^-/- Ldlr^-/- vs. Apoe^h/h Ldlr^-/- mice. The data above are pooled from two independent replicates; n = 7 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using the unpaired two-tailed Student’s t-test. Data are presented as mean ± SEM. FIG.19 shows transplantation of apoE-deficient bone marrow cells to wildtype HFD-fed AAV8-PCSK9 mice reduces leukocyte accumulation in aortas of hyperlipidemic mice. Quantification of aortic CD45⁺ cells, macrophages, and CD11b⁺ cells collected from aortas of HFD-fed 11-week-old BMT mice. Data are taken from HFD-fed 11-week-old Apoe^+/+ CD45.1 AAV8-PCSK9-injected or Apoe^-/- CD45.2 mice that received reciprocal BMT. Data are pooled from two independent experiments; n = 7 total per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIG.20 shows that systemic infusions of miR-146a mimics or miR-142a inhibitors reduce leukocyte accumulation in aortas of hyperlipidemic mice. Quantification of aortic CD45⁺ cells, macrophages, and CD11b⁺ cells collected from aortas of HFD-fed nine-week-old AAV8- PCSK9 mice injected with 1 nmol of oligonucleotides or vehicle control for four weeks. Data are taken from HFD-fed nine-week-old AAV8-PCSK9 mice. Data are pooled from two independent experiments; n = 8-10 total per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using unpaired one-way ANOVA followed by Holm-Sidak post- test. Data are presented as mean ± SEM. FIG.21 shows that modulation of microRNA-146a and -142a in the hematopoietic system using RNA mimics and antagonists, respectively, downregulates glycolytic metabolism, but improves mitochondrial metabolism that suppresses inflammation, hematopoiesis and atherosclerosis. FIG.22A-H show the biophysical parameters and immune-modulation effects of BMDM-derived exosomes. FIG.22A shows the representative concentration and size distributions of THP1-WT-exo & THP1-IL-4-exo purified from THP-1 cell culture supernatants after a 24 h period of culture as determined using nanoparticle tracking analysis. FIG.22B and FIG.22C show the average mode of particle diameter (FIG.22B) and concentration of purified exosomes in particles/mL (FIG.22C) (n = 4 samples per group). FIG.22D shows the electron micrograph of purified exosomes from BMDM. Scale bar: 50 nm. FIG.22E shows Western blot analysis of Calnexin, GM130, CD9, CD63, CD81, and apoE in exosome-free media (EFM), cell lysate, and 1.5 x 10⁹ particles of BMDM-derived exosomes (representative of three independent experiments). FIG.22F shows Western blot analysis of apoE and CD81 in EKO-BMDM-exo, WT-BMDM-exo, and mouse HDL fractionated by size-exclusion chromatography. FIG.22G shows qRT-PCR analysis of Tnfa, Il1b, Mcp1, and Il6 mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and stimulated with LPS (100 ng/mL) for 6 hours. qRT-PCR results were normalized to B2m or Gapdh, one representative experiment out of three independent replicates is shown; n = 4 per group. FIG.22H shows qRT-PCR analysis of H2-Ab1, Cd86, and Cd80 mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and stimulated with LPS (100 ng/mL) for 6 hours. qRT-PCR results were normalized to B2m or Gapdh, one representative experiment out of three independent replicates is shown; n = 4 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.23A-F show that macrophage exosomes modulate cellular apoE protein levels and suppress the phagocytic capacity of recipient macrophages. FIGS.23A-B show Western blot analysis (FIG.23A) and quantification (FIG.23B) of ApoE protein levels in cell lysates of wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIGS.23C-D show Representative histogram (FIG.23C) and quantitative graph (FIG.23D) showing MFI of CFSE-labeled apoptotic Jurkat cells uptake in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours measured by flow cytometry. FIGS.23E-F) Representative histogram (FIG.23E) and quantitative graph (FIG.23F) showing MFI of MERTK surface expression in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM- exo, or PBS for 18 hours measured by flow cytometry. One representative experiment out of two independent replicates is shown for the experiments; n = 4 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm- Sidak post-test. Data are presented as mean ± SEM. FIGS.24A-K show that ApoE expression dictates the capacity for macrophage exosomes to suppress glucose uptake and glycolysis in recipient macrophages via a miR-146a/NF-κB axis. FIG.24A is a graph showing representative Seahorse Glycolytic Rate Assay. R/AA, rotenone/antimycin A (0.5 µM) and 2-DG, 2-Deoxy-D-glucose (50 mM). FIG.24B is a graph showing quantified cell-normalized glycolysis-associated proton efflux rate (glycoPER) from the Seahorse Glycolytic Rate Assay. FIG.24C shows qRT-PCR analysis of miR-146a-5p expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM- exo, or PBS for 18 hours. FIG.24D shows qRT-PCR analysis of Irak1 and Traf6 mRNA levels in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently stimulated with LPS (100 ng/mL) for 6 hours. FIG.24E shows MFI of nuclear NF-κB phospho-p65 subunit measured by flow cytometry in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently cultured in basal or LPS-stimulated condition (100 ng/mL) for 6 hours. FIG.24F shows qRT-PCR analysis of Slc2a1 mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently cultured in basal or LPS-stimulated condition (100 ng/mL) for 6 hours. FIG.24G depicts graphs showing percentage of GLUT1⁺ cells and mean fluorescent intensity (MFI) of GLUT1 in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently stimulated with LPS (100 ng/mL) for 6 hours. FIG.24H shows 2-DG uptake assay in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT- BMDM-exo, or PBS for 18 hours and subsequently cultured in basal or LPS-stimulated condition (100 ng/mL) for 6 hours. FIG.24I shows lactate production to the conditioned media by wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently cultured in basal or LPS-stimulated condition (100 ng/mL) for 6 hours as measured by the L-Lactate Assay Kit. FIG.24J shows unannotated heatmap showing the distinct mRNA expression profiles between wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours (n = 3 per group, p <0.05). FIG.24K shows qRT-PCR analysis of Aldh2, Pkm, Cd9, Fth1, Dio2, and Pgd mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. qRT-PCR results were normalized to B2m or Gapdh for mRNA analysis and U6 snRNA or miR-16-5p for microRNA analysis. One representative experiment out of three independent replicates is shown for all experiments; n = 3-5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way or two-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.25A-P show that ApoE expression dictates the capacity for macrophage exosomes to improve mitochondrial health and functions while suppressing neutral lipids accumulation & oxidative stress in recipient macrophages. FIG.25A shows qRT-PCR analysis of Cpt1a mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM- exo, or PBS for 18 hours. FIGS.25B-C show Western blot analysis (FIG.25B) and quantification (FIG.25C) of CPT1A protein levels in cell lysates of wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIG.25D) shows qRT-PCR analysis of miR-142a-3p expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIG.25E depicts a graph showing representative Seahorse Mito Stress Assay. O, oligomycin (1 µM); F, FCCP (2 µM); and R/AA, rotenone/antimycin A (0.5 µM). FIG.25F depicts a graph showing quantified cell-normalized mitochondrial OCR from Mito Stress test. FIG.25G depicts a graph showing representative OCR measurement in response to etomoxir treatment as measured by the Agilent Seahorse instrument. Etomoxir (4 µM) and O, oligomycin (1 µM). FIG.25H depicts a graph showing quantified cell-normalized mitochondrial OCR drop upon CPT1a inhibition by etomoxir. FIG. 25I show GO enrichment analysis (Biological process) of the genes differentially expressed between wildtype BMDM exposed to EKO-BMDM-exo or WT-BMDM-exo. The minimum count of genes considered for the analysis was >10 and p <0.05. FIG.25J shows qRT-PCR analysis of Abca1, Selenow, Selenom, Selenop, Selenon, Gpx1 and Gpx3 mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIG.25K depicts a graph showing MFI of LipidTOX staining measured by flow cytometry in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM- exo, WT-BMDM-exo, or PBS for 18 hours measured by flow cytometry. FIG.25L depicts a graph showing MFI of CellROX staining measured by flow cytometry in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours measured by flow cytometry. FIGS.25M-O depict graphs showing MFI of MitoSOX (FIG.25M), Calcein AM (FIG.25N), and TMRM (FIG.25O) signals in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM- exo, or PBS for 18 hours measured by flow cytometry. FIG.25P depicts graphs showing detection of total glutathione, including reduced glutathione (GSH) and oxidized glutathione (GSSG), in Apoe^-/- BMDM or wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM- exo, WT-BMDM-exo, or PBS for 18 hours measured by flow cytometry. qRT-PCR results were normalized to B2m or Gapdh for mRNA analysis and U6 snRNA or miR-16-5p for microRNA analysis. One representative experiment out of three independent replicates is shown for the experiments; n = 3-5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way or two-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.26A-F show that EKO-BMDM-exo drives the activation and proliferation of CD4⁺ T lymphocytes. FIG.26A depicts a heatmap showing the distinct mRNA expression profiles between wildtype CD4⁺ T lymphocytes exposed to 2 x 10⁹ particles/mL of EKO- BMDM-exo, WT-BMDM-exo, or PBS for 24 hours (n = 3 per group, p <0.05) while stimulated with αCD3/αCD28 beads. FIG.26B shows GO enrichment analysis (Biological process) of the genes differentially expressed between wildtype CD4⁺ T lymphocytes exposed to EKO-BMDM- exo or WT-BMDM-exo while stimulated with αCD3/αCD28 beads. The minimum count of genes considered for the analysis was >10 and p <0.05. FIG.26C depicts Graphs showing CD4⁺ T lymphocytes proliferation measured by CFSE labeling of CD4⁺ T lymphocytes stimulated with αCD3/αCD28 beads for 4 days.2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM- exo, or PBS were added to the culture on day 1 and 3 of the experiment. FIG.26D depicts graphs showing percentage of Annexin V⁺ CD4⁺ T lymphocytes upon stimulation with αCD3/αCD28 beads for 4 days.2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS were added to the culture on day 1 and 3 of the experiment. FIG.26E depicts graphs showing MFI of CD25 and CD69 in CD4⁺ T cells co-cultured with αCD3/αCD28 beads, 5 ng/mL of murine IL-2, and 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 48 hours. FIG.26F depicts graphs showing IFN-γ⁺ cells and IFN-γ MFI in CD4⁺ T cells co- cultured with αCD3/αCD28 beads, 5 ng/mL of murine IL-2, and 2 x 10⁹ particles/mL of EKO- BMDM-exo, WT-BMDM-exo, or PBS for 12 hours. One representative experiment out of three independent replicates is shown for the experiments; n = 3-5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm- Sidak post-test. Data are presented as mean ± SEM. FIGS.27A-M show that ApoE expression dictates the capacity for macrophage exosomes to improve mitochondrial health and functions while suppressing glucose uptake, oxidative stress, activation of myeloid cells and systemic inflammation in hyperlipidemic mice. FIGS.27A-B show Images of DiR fluorescence in blood (FIG.27A) and organs (FIG.27B) 6 h post-injection from 8-week-old Western diet-fed AAV8-PCSK9-injected mice infused i.p. with PBS as control or 1 x 10¹⁰ particles of THP1-WT-exo or THP1-IL4-exo. FIG.27C shows multiplex immunoassay analysis of TNF-α, IFN-γ, IL-6, and IL-1β from plasma of Western diet- fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM- exo, WT-BMDM-exo, or PBS. FIG.27D shows heat maps representing multiplex immunoassay analysis of TNF-α, IL-6, and IL-1β cytokines released by LPS-stimulated splenic and bone marrow cells (100 ng/mL for 6 hours) from Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. Data are displayed as log₂ fold-change relative to PBS group. FIG.27E shows heat map representing qRT-PCR analysis of Tnf, Il1b, Mcp1, Il6, Arg1, Retnla, Chil3, Traf6, Irak1, Aldh2, Pkm, Cd9, Fth1, Dio2, Pgd, Cpt1a, Abca1, Selenow, Selenom, Selenop, Selenon, Gpx1 and Gpx3 mRNA expression in peritoneal macrophages of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. Data are displayed as log2 fold-change relative to PBS group. FIG.27F shows MFI of MHC-II, CD86, and CD80 expression in splenic Ly6C- MHCII⁺ CD11c⁺ cells measured by flow cytometry. FIGS.27G-K depict graphs showing MFI of 2-NBDG (FIG.27G), LipidTOX (FIG. 27H), CellROX (FIG.27I), MitoSOX (FIG.27J), and TMRM (FIG.27K) signals in circulating Ly6C^hi monocytes of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIGS.27L-M show qRT-PCR analysis of miR-146a-5p (FIG.27G) and miR-142a-3p (FIG.27H) expression in peritoneal macrophages of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. qRT-PCR results were normalized to B2m or Gapdh for mRNA analysis and U6 snRNA or miR-16-5p for microRNA analysis. One representative experiment out of two independent replicates is shown for the experiments; n = 4- 5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one- way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.28A-F show that EKO-BMDM-exo enhances hyperlipidemia-driven hematopoiesis and myelopoiesis. FIG.28A show representative plots of flow cytometric analyses of hematopoietic stem and progenitor cells in the bone marrow. FIGS.28B-C depict graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the bone marrow (FIG.28B) and spleen (FIG. 28C) of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIGS.28D-E show representative flow cytometric analyses of circulating myeloid cells (FIG.28D) and measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) (FIG.28E) in the circulation of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIG.28F show flow cytometric analyses of splenic myeloid cell subsets (monocytes, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) in the spleen of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. One representative experiment out of two independent replicates is shown for the experiments; n = 5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.29A-E show that systemic infusions of miR-146a mimics or miR-142a antagonists suppresses hyperlipidemia-driven hematopoiesis and monocytosis in Apoe^-/- mice. FIG.29A show a schematic diagram depicting the injections of RNA oligonucleotides in Western diet-fed Apoe^-/- mice. FIG.29B shows representative plots of flow cytometric analyses of hematopoietic stem and progenitor cells in the bone marrow. FIG.29C depicts graphs showing the percentages of hematopoietic stem and progenitor cell subsets (LSK, LMPP, MPP, MPP1-4, HSC, CMP, GMP, and MEP) in the bone marrow of Western diet-fed Apoe^-/- mice repeatedly infused with 1 nmol of miR-146a mimics, miR-142a inhib, or negative control. FIGS.29D-E show representative flow cytometric analyses of circulating myeloid cells (FIG.29D) and measurements of myeloid cell subsets (CD11b⁺ cells, neutrophils, Ly6C^hi monocytes, and Ly6C^lo monocytes) (FIG.29E) in the circulation of Western diet-fed Apoe^-/- mice repeatedly infused with 1 nmol of miR-146a mimics, miR-142a inhib, or negative control. Pooled data from two independent replicates is shown for the experiments; n = 8-10 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.30A-O show that EKO-BMDM-exo drives proliferation, activation, and IFN-γ release from T lymphocytes of hyperlipidemic mice via the modulation of miR-146a and miR- 142a levels. FIGS.30A-B show Representative flow cytometric analyses of circulating lymphocytes (FIG.30A) and measurements of lymphocyte subsets (CD3e⁺ T lymphocytes and B220⁺ B lymphocytes) (FIG.30B) in the circulation of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIGs.30C-H show representative flow cytometric analyses of splenic T lymphocytes (FIG.30C) and measurements of total CD4⁺ & CD8⁺ cells (FIG.30D), CD4⁺ CD69⁺ & CD8⁺ CD69⁺ cells (FIG.30E), CD4⁺ CD44⁺ CD62L- & CD8⁺ CD44⁺ CD62L- cells (T_EM) (FIG.30F), CD4⁺ CD44- CD62L⁺ & CD8⁺ CD44- CD62L⁺ cells (Tnaïve) (FIG.30G), and CD4⁺ CD44⁺ CXCR3⁺ & CD8⁺ CD44⁺ CXCR3⁺ cells (FIG.30H) in the spleens of Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIGS.30I-J show representative flow cytometric analyses of splenic Th1 and Tc1 lymphocytes (FIG.30I) and measurements of IFN-γ⁺ cells and IFN-γ MFI (FIG.30J) within the CD4⁺ and CD8⁺ T lymphocyte populations derived from Western diet-fed AAV8-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. One representative experiment out of two independent replicates is shown for all experiments; n = 5 per group. FIGS.30K-O show the measurements of total CD4⁺ & CD8⁺ cells (FIG.30K), CD4⁺ CD69⁺ and CD8⁺ CD69⁺ cells (FIG.30L), CD4⁺ CD44⁺ CD62L- & CD8⁺ CD44⁺ CD62L- cells (FIG.30M), CD4⁺ CD44- CD62L⁺ and CD8⁺ CD44- CD62L⁺ cells (FIG.30N), and CD4⁺ CD44⁺ CXCR3⁺ & CD8⁺ CD44⁺ CXCR3⁺ cells (FIG.30O) in the lymph nodes of Western diet-fed Apoe^-/- mice repeatedly infused with 1 nmol of miR-146a mimics, miR-142a inhibitor, or negative control. Pooled data from two independent replicates is shown for the experiments; n = 8-10 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.31A-E show the characterization and in vitro uptake of BMDM exosomes in recipient macrophages. FIG.31A show the exosomes secretion rate (x 10⁹ particles) per million cells over a 24-hour incubation period as detected by NTA. FIG.31B shows protein measurements in exosome-containing fractions isolated from conditioned media of BMDM macrophages. n = 4 per group. FIGS.31C-D show merged images (FIG.31C) and quantification (FIG.31D) of the internalization of PKH26-labeled BMDM-derived exosomes by naive primary BMDM counterstained with Hoechst (blue). BMDM were co-incubated with 2 x 10⁹ PKH26- labeled exosomes for 2 h at 37^oC and washed repeatedly to remove unbound exosomes. The images were acquired using a Zeiss Axio microscope system with a 20x objective (n = 4 samples per group, representative of two independent experiments). Scale bar: 100 μm. (E) qRT- PCR analysis of Apoe mRNA expression in wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. qRT-PCR results were normalized to B2m or Gapdh. One representative experiment out of three independent replicates is shown for the experiments; n = 4 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.32A-E show that ApoE expression dictates the capacity for macrophage exosomes to downregulate the expression of genes involved in glucose uptake and glycolytic activity in recipient BMDC. FIG.32A show the qRT-PCR analysis of miR-146a-5p expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIG.32B shows the qRT-PCR analysis of Irak1 and Traf6 mRNA levels in wildtype BMDC exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently stimulated with LPS (100 ng/mL) for 6 hours. FIG.32C shows qRT-PCR analysis of Slc2a1 mRNA expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO- BMDM-exo, WT-BMDM-exo, or PBS for 18 hours and subsequently cultured in basal or LPS- stimulated condition (100 ng/mL) for 6 hours. FIG.32D shows the annotated heatmap showing the distinct mRNA expression profiles between wildtype BMDM exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours (n = 3 per group, p <0.05). FIG.32E shows the qRT-PCR analysis of Aldh2, Pkm, Cd9, Fth1, Dio2, and Pgd mRNA expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. qRT-PCR results were normalized to B2m or Gapdh for mRNA analysis and U6 snRNA or miR-16-5p for microRNA analysis. One representative experiment out of three independent replicates is shown for all experiments; n = 4 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm- Sidak post-test. Data are presented as mean ± SEM. FIGS.33A-C show that ApoE expression dictates the capacity for macrophage exosomes to enhance the expression of genes involved in FAO, OxPHOS, lipid transport, and oxidative stress response in recipient BMDC. FIG.33A shows qRT-PCR analysis of Cpt1a mRNA expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM- exo, or PBS for 18 hours. FIG.33B show that the qRT-PCR analysis of miR-142a-3p expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIG.33C show qRT-PCR analysis of Abca1, Selenow, Selenom, Selenop, Selenon, Gpx1 and Gpx3 mRNA expression in wildtype BMDC exposed to 2 x 10⁹ particles of EKO- BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. qRT-PCR results were normalized to B2m or Gapdh for mRNA analysis and U6 snRNA or miR-16-5p for microRNA analysis. One representative experiment out of three independent replicates is shown for the experiments; n = 4 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one- way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.34A-C show the lipid profiles of Western diet-fed AAV-PCSK9 mice infused with EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIGS.34A-B show fasting plasma cholesterol (FIG.34A) and triglycerides (FIG.34B) in Western diet-fed AAV-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM-exo, WT-BMDM-exo, or PBS. FIG. 34C show the cholesterol measurements in FPLC fractions from collected plasma of Western diet-fed AAV-PCSK9-injected mice repeatedly infused with 1 x 10¹⁰ particles of EKO-BMDM- exo, WT-BMDM-exo, or PBS. One representative experiment out of two independent replicates is shown for the experiments; n = 5 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. FIGS.35A-B show the biodistribution of DiR-labeled BMDM exosomes upon infusion into Western diet-fed AAV-PCSK9 mice. FIGS.35A-B depict images of DiR fluorescence in blood (FIG.35A) and organs (FIG.35B) 6 h post-injection from 8-week-old Western diet-fed AAV-PCSK9-injected mice infused i.p. with PBS as control or 1 x 10¹⁰ particles of EKO- BMDM-exo or WT-BMDM-exo. FIGS.36A-B show the gating strategy for flow cytometric analysis of splenic HSPC and myeloid cells. FIGS.36A-B show the representative flow cytometry plots of splenic hematopoietic stem/progenitor cell subsets (FIG.36A) and myeloid cell subsets (FIG.36B). FIGS.37A-C show that infusions of RNA oligonucleotides regulated cellular miR-146a- 5p and miR-142a-3p without altering plasma cholesterol levels. FIG.37A shows the fasting plasma cholesterol in Western diet-fed Apoe^-/- mice repeatedly infused with 1 nmol of miR-146a mimics, miR-142a inhibitors, or negative control. FIGS.37B-C show qRT-PCR analysis of miR-146a-5p (FIG.37B) and miR-142a-3p (FIG.37C) expression in peritoneal macrophages of Western diet-fed Apoe^-/- mice repeatedly infused with 1 nmol of miR-146a mimics, miR-142a inhibitors, or negative control. Pooled data from two independent replicates is shown for the experiments; n = 5-10 per group. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 as determined using one-way ANOVA followed by Holm-Sidak post-test. Data are presented as mean ± SEM. DETAILED DESCRIPTION The present disclosure can be understood more readily by reference to the following detailed description of the invention, the figures and the examples included herein. Before the present compositions and methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described. Moreover, it is to be understood that unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, and the number or type of aspects described in the specification. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. Definitions As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The word “or” as used herein means any one member of a particular list and also includes any combination of members of that list. Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. In particular, in methods stated as comprising one or more steps or operations it is specifically contemplated that each step comprises what is listed (unless that step includes a limiting term such as “consisting of”), meaning that each step is not intended to exclude, for example, other additives, components, integers or steps that are not listed in the step. Ranges can be expressed herein as from “about” or “approximately” one particular value, and/or to “about” or “approximately” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” or “approximately,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value "10" is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances where it does not. As used herein, the term “subject” refers to the target of administration, e.g., a human. Thus, the subject of the disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). In one aspect, a subject is a mammal. In another aspect, the subject is a human. The term does not denote a particular age or sex. Thus, adult, child, adolescent and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. As used herein, the term "patient" refers to a subject afflicted with a disease or disorder. The term "patient" includes human and veterinary subjects. In some aspects of the disclosed methods, the “patient” has been diagnosed with a need for treatment for cardiometabolic inflammation, atherosclerosis, or cardiac failure, such as, for example, prior to the administering step. By “treat” is meant to administer a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof or composition of the invention to a subject, such as a human, that has an increased susceptibility for developing a disease, disorder or infection (e.g., cardiometabolic inflammation, atherosclerosis, or cardiac failure, diabetes, cardiometabolic disease, chronic inflammatory disorder, cardiac inflammation, hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease) in order to prevent or delay onset of the disease, disorder, prevent or delay a worsening of the effects of the disease, or disorder, or to partially or fully reverse the effects of the disease or disorder. In some aspects, treat can mean to ameliorate a symptom of a disease or disorder. As used herein, the terms “disease” or “disorder” or “condition” are used interchangeably referring to any alternation in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder or condition can also related to a distemper, ailing, ailment, malady, disorder, sickness, illness, complaint, affection. By “prevent” is meant to minimize the chance that a subject who has an increased susceptibility for developing a disease or disorder will actually develop the disease, disorder or infection. As used herein, the terms “administering” and “administration” refer to any method of providing a disclosed composition of the invention or a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof to a subject. Such methods are well known to those skilled in the art and include, but are not limited to: oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition. In some aspects, the skilled person can determine an efficacious dose, an efficacious schedule, or an efficacious route of administration for a disclosed composition or a disclosed miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof so as to treat a subject. The terms "vector" or “construct” refer to a nucleic acid sequence capable of transporting into a cell another nucleic acid to which the vector sequence has been linked. The term "expression vector" includes any vector, (e.g., a plasmid, cosmid or phage chromosome) containing a gene construct in a form suitable for expression by a cell (e.g., linked to a transcriptional control element). "Plasmid" and "vector" are used interchangeably, as a plasmid is a commonly used form of vector. Moreover, the invention is intended to include other vectors which serve equivalent functions. The term “expression vector” is herein to refer to vectors that are capable of directing the expression of genes to which they are operatively-linked. Common expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. Recombinant expression vectors can comprise a nucleic acid as disclosed herein in a form suitable for expression of the acid in a host cell. In other words, the recombinant expression vectors can include one or more regulatory elements or promoters, which can be selected based on the host cells used for expression that is operatively linked to the nucleic acid sequence to be expressed. “Promote,” “promotion,” and “promoting” refer to an increase in an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the initiation of the activity, response, condition, or disease. This may also include, for example, a 10% increase in the activity, response, condition, or disease as compared to the native or control level. Thus, in an aspect, the increase or promotion can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or more, or any amount of promotion in between compared to native or control levels. In an aspect, the increase or promotion is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or 90-100% as compared to native or control levels. In an aspect, the increase or promotion is 0- 25, 25-50, 50-75, or 75-100%, or more, such as 200, 300, 500, or 1000% more as compared to native or control levels. In an aspect, the increase or promotion can be greater than 100 percent as compared to native or control levels, such as 100, 150, 200, 250, 300, 350, 400, 450, 500% or more as compared to the native or control levels. As used herein, promoting can also mean enhancing. As used herein, the term “inhibit" or “inhibiting” mean decreasing hematopoiesis or myelopoiesis, for example, decreasing the rate of blood cell production or the rate of development of myeloid immune cells, respectively, from the rate that would occur without treatment. All publications and patent applications mentioned in the specification are indicative of the level of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, certain changes and modifications may be practiced within the scope of the appended claims. Apolipoprotein E (ApoE), a 34 kDa glycoprotein expressed as three common isoforms by numerous cell types, was first recognized for its ability to control plasma triglyceride and cholesterol homeostasis (Mahley RW. Science.1988;240(4852):622-30; and Weisgraber KH. Adv Protein Chem.1994;45(249-302). Numerous studies also identified the importance of the cellular source of ApoE expression for its effective clearance of plasma lipoproteins (Hasty AH, et al. J Lipid Res.1999;40(8):1529-38; and Raffai RL, et al. J Biol Chem.2003;278(13):11670- 5). Increasingly, ApoE is appreciated for its growing number of pleiotropic properties that together contribute to cellular health and dysfunction including in the cardiovascular system (Davignon J. Arterioscler Thromb Vasc Biol.2005;25(2):267-9; and Bouchareychas L, and Raffai RL. J Cardiovasc Dev Dis.2018;5(2)). Beyond serving as a ligand for remnant lipoprotein receptors on the surface of liver hepatocytes (Mahley RW, and Ji ZS. J Lipid Res. 1999;40(1):1-16), ApoE is also known to modulate both innate and adaptive immunity to control chronic inflammation in atherosclerosis (Curtiss LK, and Boisvert WA. Curr Opin Lipidol. 2000;11(3):243-51). This property of ApoE is thought to be distinct from its capacity to protect against hyperlipidemia-driven inflammation and atherosclerosis (Linton MF, et al. Science. 1995;267(5200):1034-7; Boisvert WA, et al. J Clin Invest.1995;96(2):1118-24; and Ma Y, et al. PLoS One.2008;3(6):e2503). Furthermore, studies revealed a capacity for ApoE to promote the regression of atherosclerosis beyond correcting plasma cholesterol levels (Raffai RL, et al. Arterioscler Thromb Vasc Biol.2005;25(2):436-41). Knowledge derived from these extensive studies using diverse mouse models of cell- specific and conditional ApoE expression identified myeloid-derived ApoE expression as important to its ability to control atherosclerosis (Fazio S, et al. J Lipid Res.2002;43(10):1602- 9; and Gaudreault N, et al. PLoS One.2012;7(5):e35816). A mechanism identified as central for ApoE to control macrophage foam cell formation and adaptive immune inflammation in atheroma centered on its ability to prevent cellular lipid excess by promoting its efflux to high- density lipoproteins (Bonacina F, et al. Nat Commun.2018;9(1):3083; and Bellosta S, et al. J Clin Invest.1995;96(5):2170-9). ApoE’s ability to prevent cellular lipid excess in hematopoietic stem and progenitor cells was subsequently identified as an important checkpoint in controlling extramedullary hematopoiesis and monocytosis in the setting of hyperlipidemia (Murphy AJ, et al. J Clin Invest. 2011;121(10):4138-49). By preventing an over-accumulation of cholesterol in the plasma membrane, ApoE was shown to control the clustering of cytokine receptor complexes in lipid rafts and subsequent proliferative signaling in hematopoiesis (Murphy AJ, et al. J Clin Invest. 2011;121(10):4138-49; and Wang M, et al. Arterioscler Thromb Vasc Biol.2014;34(5):976-84). More recent studies investigated ApoE isoform-specific properties in myeloid-cell derived inflammation and atherosclerosis susceptibility (Bonacina F, et al. Nat Commun. 2018;9(1):3083; and Igel E, et al. J Biol Chem.2021;297(3):101106). In one study, ApoE expression in dendritic cells prevented cholesterol excess in the plasma membrane that controlled antigen presentation and co-stimulation of T cells (Bonacina F, et al. Nat Commun. 2018;9(1):3083). Importantly, findings from that study highlighted ApoE4 as less potent than ApoE3 in mediating this protective immune-regulatory property (Bonacina F, et al. Nat Commun.2018;9(1):3083). Findings from another study examined ApoE isoform specific properties in controlling macrophage activation and atherosclerosis susceptibility (Igel E, et al. J Biol Chem.2021;297(3):101106). While ApoE2 expression by macrophages was found to accelerate atherosclerosis due to impaired cellular lipid efflux that led to NLRP3 inflammasome activation and myelopoiesis, ApoE4 expression accelerated atherosclerosis due to increased cellular oxidative stress (Igel E, et al. J Biol Chem.2021;297(3):101106). While these observations sparked a renewed appreciation for the immune regulatory properties of ApoE isoforms in myeloid cells, details of their mechanistic mode of action remain elusive. To address this gap in knowledge, a study reported an ability for ApoE to modulate the biogenesis and activity of miR-146a (Li K, et al. Circ Res.2015;117(1):e1-e11), which is recognized for its role in controlling NF-κB signaling and inflammatory cytokine signaling in the hematopoietic system (Li K, et al. Circ Res.2015;117(1):e1-e11; Taganov KD, et al. Proc Natl Acad Sci U S A.2006;103(33):12481-6; and Boldin MP, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med.2011;208(6):1189- 201). Results of this study revealed that inflammatory excess displayed by myeloid cells of Apoe^-/- mice could be corrected by the delivery of miR-146a mimics that was effective in controlling atherosclerosis without plasma lipid correction (Li K, et al. Circ Res. 2015;117(1):e1-e11). Described herein is the broader impact of cell intrinsic ApoE expression on altering the microRNA repertoire of macrophages and testing whether this modulation extended to dendritic cells to restrict adaptive immune cell activation. It was also tested whether microRNA controlled by ApoE could regulate cellular glycolytic metabolism and oxidative phosphorylation, two metabolic processes increasingly recognized to play roles in driving and resolving inflammation in atherosclerosis (Koelwyn GJ, et al. Nat Immunol.2018;19(6):526-37; and Tabas I, and Bornfeldt KE. Circ Res.2020;126(9):1209-27). Results described herein provide evidence supporting a role for ApoE in controlling immunometabolism in myeloid cells and their hematopoietic stem and progenitor cells (HSPC) by increasing levels of miR-146a and reducing those of miR-142a that are shown to restrict cellular glucose uptake and glycolytic activity while enhancing fatty acid oxidation and oxidative phosphorylation, respectively, (see, for example, FIG.21). Together, these findings demonstrate the influence that ApoE exerts on cellular metabolism in myeloid cells to control cardiovascular inflammation and atherosclerosis. Cardiometabolic inflammation develops as a consequence of metabolic excess that drives an expansion of immune cells in the blood as well as in tissues that include arteries, fat tissues and the liver. Such immune cells cause inflammatory changes in the tissues that contribute to many types of diseases including, but not limited to atherosclerosis, diabetes and fatty liver disease. As described in the Examples, systemic injections of, for example, synthetic RNA inhibitors of microRNA-142a show that cardiometabolic inflammation in diabetic mice can be controlled. Further, data disclosed herein provide evidence that the use of a miR-146a agonist in can suppress NF-kB driven cellular glucose uptake and its glycolytic metabolism in myeloid cells thereby reducing their propensity to secrete inflammatory cytokines promote systemic and tissue inflammation that are recognized to contribute to the pathogenesis of cardiometabolic inflammation, diabetes, atherosclerosis and cardiac dysfunction. Also disclosed herein are data that demonstrate that the use of a miR-142a antagonist in can increase cellular levels of CTP1a, an enzyme that plays an important role in driving fatty acid oxidation in the mitochondria of myeloid cells. By increasing cellular levels of CTP1a, oxidative phosphorylation can be enhanced which promotes anti-inflammatory activities including but not limited to tissue repair, lipid efflux and protective cytokine production (e.g., IL-10). IL-10 is a cytokine involved in suppressing inflammation in cardiometabolic disease and restoring insulin activity in diabetes. Apo E, plays a role in controlling levels of cholesterol-rich lipoproteins in plasma, thereby protecting against atherosclerosis and cardiovascular disease (Mahley RW. Science. 1988;240(4852):622-30; and Weisgraber KH. Adv Protein Chem.1994;45(249-3021, 2), and is recognized for its ability to exert pleiotropic properties to maintain tissue homeostasis (Davignon J. Arterioscler Thromb Vasc Biol.2005;25(2):267-9), including a capacity to regulate immune cell activity and inflammation (Curtiss LK, and Boisvert WA. Curr Opin Lipidol. 2000;11(3):243-51). While its expression is restricted to myeloid cells, apoE exerts a control over numerous types of leukocytes through paracrine mechanisms that remain incompletely understood (Bonacina F, et al. Nat Commun.2018;9(1):3083; Igel E, et al. J Biol Chem. 2021;297(3):101106; He Y, et al. J Clin Invest.2021;131(3); and Riddell DR, et al. J Biol Chem.1997;272(1):89-95)). Macrophages, the second most important cellular source of apoE expression in mammals, are recognized to contribute up to 10% of apoE in plasma (Hasty AH, et al. J Lipid Res.1999;40(8):1529-38; and Linton MF, et al. J Clin Invest.1991;88(1):270-81). While this source of apoE expression has been shown to protect against atherosclerosis by enhancing plasma lipoprotein clearance (Linton MF, et al. Science.1995;267(5200):1034-7; and Boisvert WA, et al. J Clin Invest.1995;96(2):1118-24), numerous other pathways have emerged. Macrophage apoE expression improves cellular cholesterol efflux (Rosenson RS, et al. Circulation.2012;125(15):1905-19) and the phagocytic uptake of apoptotic cells (Grainger DJ, et al. J Immunol.2004;173(10):6366-75), while also reducing the expression of inflammatory cytokines (Curtiss LK, and Boisvert WA. Curr Opin Lipidol.2000;11(3):243-51) and co- stimulatory molecules on the cell surface (Bonacina F, et al. Nat Commun.2018;9(1):3083; and Tenger C, and Zhou X. Immunology.2003;109(3):392-7) that together limit lesion inflammation. Studies also revealed that apoE expression in hematopoietic stem and progenitor cells (HSPC) in the bone marrow and spleen restricts myelopoiesis by limiting receptor complexes in cholesterol-rich lipid rafts in the plasma membrane, which reduces proliferative signaling (Murphy AJ, et al. J Clin Invest.2011;121(10):4138-49). Furthermore, apoE expression in macrophages has recently been identified to regulate microRNA-controlled NF-κB signaling to limit inflammatory cytokine production and atherosclerosis in mice with hyperlipidemia (Li K, et al. Circ Res.2015;117(1):e1-e11). Although cytokines produced by macrophages are recognized to differentially modulate inflammation and its resolution in hyperlipidemia and atherosclerosis (Moore KJ, et al. Nat Rev Immunol.2013;13(10):709-21), extracellular vesicles (EVs) including exosomes have recently emerged as a source of intercellular signaling (Bouchareychas L, et al. Cell Rep. 2020;32(2):107881; Bouchareychas L, et al. iScience.2021;24(8):102847; and Nguyen MA, et al. Arterioscler Thromb Vasc Biol.2018;38(1):49-63). Indeed, studies have shown that exosomes produced by macrophages can differentially control inflammatory properties in recipient cells, including in models of cancer (Zheng P, et al. T Cell Death Dis.2018;9(4):434), atherosclerosis (Bouchareychas L, et al. Cell Rep.2020;32(2):107881; and Bouchareychas L, et al. iScience.2021;24(8):102847), and obesity (Phu TA, et al. Mol Ther.2022;30(6):2274-97). Macrophage apoE expression is recognized to play a central role in modulating cellular inflammatory and tissue-reparative properties. As described herein, it was tested whether it also controls the production and cell signaling properties of exosomes in the context of hyperlipidemia. The findings disclosed herein show that while a loss of apoE expression does not alter the rate or size of exosome secretion by cultured macrophages, it substantially impacts their cellular signaling properties. For example, exosomes produced by Wildtype macrophages (WT- BMDM-exo) communicated anti-inflammatory properties by driving fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient myeloid cells. In contrast, exosomes produced by Apoe-/- macrophages (EKO-BMDM-exo) communicated inflammatory signaling by increasing glycolysis and oxidative stress. Unlike WT-BMDM-exo that resolved systemic inflammation when infused into hyperlipidemic mice, the infusion of EKO-BMDM-exo increased hematopoiesis and activated myeloid cells and T lymphocytes. Together, the findings disclosed herein show that macrophage apoE expression serves to control immunity and limit inflammation in hyperlipidemia. COMPOSITIONS Disclosed herein are compositions for use in methods of reducing cardiometabolic inflammation, treating or preventing atherosclerosis, treating, preventing, or reducing cardiac failure in subjects with hyperlipidemia type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease treating or suppressing inflammation caused by hyperlipidemia, increasing plasma IL-10 levels, enhancing fatty acid oxidation and oxidative phosphorylation, decreasing hematopoiesis, decreasing myelopoiesis, decreasing aortic leukocyte accumulation, and suppressing glycolysis and oxidative stress in immune cells in subjects in need thereof by administering miR-146a agonists or mimics, miR-142 antagonists, or combinations thereof. In some aspects, the compositions can comprise miR-146a agonists or mimics, miR-142 antagonists, or combinations thereof. MicroRNAs (miRNAs or MiRs) are a class of small (e.g., about 20 nucleotides in length), conserved non-coding RNAs that regulate mRNA degradation and translation, at least in part through binding to the 3'UTR of target genes. In some aspects, the miR can be miR-146a, and the target genes can be the TRAF6 gene and/or the IRAK1 gene. In some aspects, the miR can be miR-142a, and the target gene can be the CPT1A gene. In some aspects, miR-146 can be miR-146a. In some aspects, miR-146 can be miR-146b. In some aspects the miR-146 agonist or mimic, can be a miR-146a agonist or mimic. In some aspects the miR-146 agonist or mimic, can be a miR-146b agonist or mimic. In some aspects, miR-146a can be miR-146-5p. In some aspects, miR-146a can be hsa- miR-146-5p. In some aspects, miR-146-5p can be miR-146a-5p or has miR-146a-5p. In some aspects, the hsa miR-146-5p can comprise the nucleotide sequence UGAGAACUGAAUUCCAUGGGUU (SEQ ID NO: 1). In some aspects, the stem loop sequence for hsa-miR-146a (human) can be the nucleotide sequence CCGAUGUGUAUCCUCAGCUUUGAGAACUGAAUUCCAUGGGUUGUGUCAGUGUCA GACCUCUGAAAUUCAGUUCUUCAGCUGGGAUAUCUCUGUCAUCGU (SEQ ID NO: 2). In some aspects, the stem loop sequence for mmu-miR-146a (mouse) can be the nucleotide sequence AGCUCUGAGAACUGAAUUCCAUGGGUUAUAUCAAUGUCAGACCUGUGAAAUUCA GUUCUUCAGCU (SEQ ID NO: 3). The mature sequence for mmu-miR-146a-5p can be the nucleotide sequence UGAGAACUGAAUUCCAUGGGUU (SEQ ID NO: 1; same as human mature sequence). In some aspects, the composition can comprise a sequence derived from miR- 146a-5p. In some aspects, the miR-146a-5p can consist of the nucleotide sequence UGAGAACUGAAUUCCAUGGGUU (SEQ ID NO: 1). In some aspects, the composition can consist of a sequence derived from miR-146a-5p. In some aspects, the term “miR-146a-5p” can also include fragments of the miR-146a-5p molecule. As used herein, the term “fragment” refers to a portion of the full-length miR-146a- 5p. The size of the fragment can vary and must include a functional fragment, that is, the fragment must be able to modulate the expression of TRAF6 gene and/or the IRAK1 gene and NF-kB or components of the glycolysis including the glucose transporter GluT1 and/or fatty acid or oxidative phosphorylation signaling pathways as described herein. Typically, the fragment can comprise at least the seed region sequence GAGAACU (SEQ ID NO: 4). In some aspects, the miR-146a or miR-146a-5p agonist can be a double-stranded RNA molecule. In some aspects, the miR-146a or miR-146a-5p agonist can be a double-stranded RNA molecule containing the functional guide strand (used by Ago protein to target mRNAs) and the non-functional passenger strand. In some aspects, miR-142 can be miR-142a. In some aspects, miR-142 can be miR-142b. In some aspects the miR-146 agonist or mimic, can be a miR-146a agonist or mimic. In some aspects the miR-146 agonist or mimic, can be a miR-146b agonist or mimic. In some aspects, miR-142a can be miR-142-3p. In any of the embodiments described herein, miR-142a can be miR-142-3p. In some aspects, miR-142-3p can refer to has-miR-142- 3p. As used herein, “miR-142-3p” refers to a microRNA having the sequence 5′- GACAGUGCAGUCACCCAUAAAGUAGAAAGCACUACUAACAGCACUGGAGGGUGU AGUGUUUCCUACUUUAUGGAUGAGUGUACUGUG-3′ (SEQ ID NO: 5; human (has-miR- 142-3p)) or ACCCAUAAAGUAGAAAGCACUACUAACAGCACUGGAGGGUGUAGUGUUUCCUAC UUUAUGGAUG (SEQ ID NO: 6; human (hsa-miR-142-3p)). In some aspects, the seed match region of miR-142-5p comprises nucleotides 1 to 9, nucleotides 1 to 8, nucleotides 1 to 7, nucleotides 2 to 9, nucleotides 2 to 8, or nucleotides 2 to 7. As used herein, “miR-142-3p” refers to a microRNA having the sequence 5′- UGUAGUGUUUCCUACUUUAUGGA-3′ (SEQ ID NO: 7). In some aspects, the seed match region of miR-142-3p comprises nucleotides 1 to 9, nucleotides 1 to 8, nucleotides 1 to 7, nucleotides 2 to 9, nucleotides 2 to 8, or nucleotides 2 to 7. In some aspects, an oligonucleotide that comprises a region that is complementary to miR-142 is referred to as a miR-142 antagonist. PHARMACEUTICAL COMPOSITIONS As disclosed herein, are pharmaceutical compositions, comprising a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof and a pharmaceutical acceptable carrier described herein. In some aspects, a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be formulated for systemic or parental administration. In some aspects, the parental administration can intravenous, subcutaneous, or intramuscular. The compositions can be formulated for administration by any of a variety of routes of administration, and can include one or more physiologically acceptable excipients, which can vary depending on the route of administration. As used herein, the term “excipient” means any compound or substance, including those that can also be referred to as “carriers” or “diluents.” Preparing pharmaceutical and physiologically acceptable compositions is considered routine in the art, and thus, one of ordinary skill in the art can consult numerous authorities for guidance if needed. The compositions can be administered directly to a subject. Generally, the compositions can be suspended in a pharmaceutically acceptable carrier (e.g., physiological saline or a buffered saline solution) to facilitate their delivery. Encapsulation of the compositions in a suitable delivery vehicle (e.g., polymeric microparticles or implantable devices) may increase the efficiency of delivery. The compositions can be formulated in various ways for parenteral or nonparenteral administration. Where suitable, oral formulations can take the form of tablets, pills, capsules, or powders, which may be enterically coated or otherwise protected. Sustained release formulations, suspensions, elixirs, aerosols, and the like can also be used. Pharmaceutically acceptable carriers and excipients can be incorporated (e.g., water, saline, aqueous dextrose, and glycols, oils (including those of petroleum, animal, vegetable or synthetic origin), starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monosterate, sodium chloride, dried skim milk, glycerol, propylene glycol, ethanol, and the like). The compositions may be subjected to conventional pharmaceutical expedients such as sterilization and may contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like. Suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, which is herein incorporated by reference. Such compositions will, in any event, contain an effective amount of the compositions together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the patient. The pharmaceutical compositions as disclosed herein can be prepared parenteral administration. Pharmaceutical compositions prepared for parenteral administration include those prepared for intravenous (or intra-arterial), intramuscular, subcutaneous, intraperitoneal, transmucosal (e.g., intranasal, intravaginal, or rectal), or transdermal (e.g., topical) administration. Aerosol inhalation can also be used. Thus, compositions can be prepared for parenteral administration that includes a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof dissolved or suspended in an acceptable carrier, including but not limited to an aqueous carrier, such as water, buffered water, saline, buffered saline (e.g., PBS), and the like. One or more of the excipients included can help approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like. Where the compositions include a solid component (as they may for oral administration), one or more of the excipients can act as a binder or filler (e.g., for the formulation of a tablet, a capsule, and the like). The pharmaceutical compositions can be sterile and sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation, which is encompassed by the present disclosure, can be combined with a sterile aqueous carrier prior to administration. The pH of the pharmaceutical compositions typically will be between 3 and 11 (e.g., between about 5 and 9) or between 6 and 8 (e.g., between about 7 and 8). The resulting compositions in solid form can be packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules. In some aspects, a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be administered systemically. In some aspects, a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be administered intravenously, intramuscularly, or subcutaneously. In some aspects, the composition can be formulated in a lipid emulsion (e.g., emulsified in a phospholipid). In some aspects, the a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be formulated for delivery in a lipid emulsion, a liposome, a nanoparticle, an exosome, or in a viral vector. The liposome can be a unilamellar, multilamellar, or multivesicular liposome. A wide variety of liposomes and exosomes can be used. For example, in some aspects, a silicone nanoparticle can be used to deliver a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof to a cell. In some aspects, a nanovector can be used to deliver a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof to a subject. In some aspects, miR-146a agonist or mimic can be encoded by a nucleic acid. In some aspects, the miRNA-142 antagonist can be encoded by a nucleic acid. The nucleic acid can be transfected into one or more cells. The transfection can comprise electroporation or incubation with a viral vector. In some aspects, the nucleic acid can be located in a vector. In some aspects, the vector can be plasmid, cosmid, phagemid or a viral vector. In some aspects, the vector can comprise a lipid, lipid emulsion, liposome, nanoparticle or exosomes. In some aspects, nucleic acid can be comprised in a lipid, lipid emulsion, liposome, nanoparticle or exosome. In some aspects, viral vector can be an adenovirus, an adeno-associated virus, a lentivirus or a herpes virus. In some aspects, the vector can comprise a lipid, lipid emulsion, liposome, nanoparticle or exosomes. In some aspects, a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be conjugated to copolymer. Traditional copolymers have been used in numerous laboratories worldwide and also in several clinical trials. (See U.S. Patent No.5,037,883, which is hereby incorporated by reference in its entirety). For example, N-(2- hydroxypropyl)methacrylamide) (HPMA) copolymers are: (1) biocompatible and have a well- established safety profile; (2) water-soluble and have favorable pharmacokinetics when compared to low molecular weight (free, non-attached) drugs; and (3) possess excellent chemistry flexibility (i.e., monomers containing different side chains can be easily synthesized and incorporated into their structure). However, HPMA polymers are not degradable and the molecular weight of HPMA polymers should be kept below the renal threshold to sustain biocompatibility. This limits the intravascular half-life and accumulation of HPMA polymers in solid tumor via the EPR (enhanced permeability and retention) effect. A backbone degradable HPMA copolymer carrier can be used to overcome limitations associated with HPMA. The copolymer carrier can contain enzymatically degradable sequences (i.e., by Cathepsin B, matrix matalloproteinases, etc.) in the main chain (i.e., the polymer backbone) and enzymatically degradable side chains (i.e., for drug release). (See, e.g., U.S. Patent Application No.13/583,270, which is hereby incorporated by reference in its entirety). Upon reaching the lysosomal compartment of cells, the drug can be released and concomitantly the polymer carrier can be degraded into molecules that are below the renal threshold and can be eliminated from the subject. Thus, diblock or multiblock biodegradable copolymers with increased molecular weight can be produced. This can further enhance the blood circulation time of the copolymer-a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof therapeutic conjugate disclosed herein, which is favorable for drug-free macromolecular therapeutics targeting, for example, circulating cancer cells. Furthermore, U.S. Patent 4,062,831 describes a range of water-soluble polymers and U.S. Patent No.5,037,883 describes a variety of peptide sequences, both of which are hereby incorporated by reference in their entireties. In some instances, the a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be conjugated to HPMA copolymers administered in the disclosed methods can comprise 2, 3, 4, 5, 6, 7, 8, 9, or 10 HPMA copolymers. In some instances, each HPMA copolymer can be connected via enzymatically degradable peptides. In some aspects, the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can be conjugated to HPMA copolymers administered in the disclosed methods can also comprise a linker. In some aspects, the linker can be a peptide linker. Vectors can include plasmids, cosmids, and viruses (e.g., bacteriophage, animal viruses, and plant viruses), and artificial chromosomes (e.g., YACs). Vectors can comprise targeting molecules. A targeting molecule is one that directs the desired nucleic acid to a particular organ, tissue, cell, or other location in a subject's body. A vector, generally, brings about replication when it is associated with the proper control elements (e.g., a promoter, a stop codon, and a polyadenylation signal). Examples of vectors that are routinely used in the art include plasmids and viruses. The term “vector” includes expression vectors and refers to a vector containing a nucleic acid sequence coding for at least part of a gene product capable of being transcribed. A variety of ways can be used to introduce an expression vector into cells. In an aspect, the expression vector comprises a virus or an engineered vector derived from a viral genome. As used herein, “expression vector” is a vector that includes a regulatory region. A variety of host/expression vector combinations can be used to express the nucleic acid sequences disclosed herein. Examples of expression vectors include but are not limited to plasmids and viral vectors derived from, for example, bacteriophages, retroviruses (e.g., lentiviruses), and other viruses (e.g., adenoviruses, poxviruses, herpesviruses and adeno-associated viruses). Vectors and expression systems are commercially available and known to one skilled in the art. M^ETHODS Disclosed herein, are methods of reducing cardiometabolic inflammation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the subject has hyperlipidemia. In some aspects, the subject has type II diabetes. Disclosed herein, are methods of treating or preventing atherosclerosis in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the subject has hyperlipidemia. In some aspects, the subject has type II diabetes. Disclosed herein, are methods of treating systemic inflammation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the subject has hyperlipidemia. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146b agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the subject has type II diabetes. Disclosed herein, are methods of treating, preventing, or reducing cardiac failure in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of treating or suppressing systemic and tissue inflammation caused by hyperlipidemia in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of increasing plasma IL-10 levels in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of enhancing fatty acid oxidation and oxidative phosphorylation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of enhancing fatty acid oxidation and oxidative phosphorylation in one or more immune cells, hematopoietic stem cells, or progenitor cells. In some aspects, the methods can comprise administering to a subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the subject has or is suffering from cardiometabolic inflammation. Disclosed herein, are methods of decreasing hematopoiesis in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the number of monocytes and/or neutrophils in the circulation or the spleen of the subject can be reduced, thereby controlling inflammation by reducing pro-inflammatory cell types and pro- inflammatory cytokines. In some aspects, the subject has hyperlipidemia. In some aspects, the hematopoiesis is hyperlipidemia-driven. Disclosed herein, are methods of decreasing myelopoiesis in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the number of monocytes and/or neutrophils in the circulation or the spleen of the subject can be reduced, thereby controlling inflammation by reducing pro-inflammatory cell types and pro- inflammatory cytokines. In some aspects, the subject has hyperlipidemia. In some aspects, the hematopoiesis is hyperlipidemia-driven. Disclosed herein, are methods of decreasing aortic leukocyte accumulation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of decreasing T lymphocyte activation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of decreasing T lymphocyte activation in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146 agonist or mimic, a miR-142 antagonist, or a combination thereof. Disclosed herein, are methods of suppressing glycolysis and oxidative stress in immune cells. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the immune cells can be macrophages or blood monocytes. In some aspects, the immune cells can be hematopoietic stem cells or progenitor cells of the macrophages or the blood monocytes. Disclosed herein, are methods of decreasing inflammatory cytokines in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In any of the methods disclosed herein, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or a combination thereof can decrease one or more pro-inflammatory markers. In some aspects, the one or more pro- inflammatory markers can be decreased in tissue macrophages or blood monocytes. In some aspects, the one or more pro-inflammatory markers can be TNF ^, IL-6 IL-1 ^, MCP1, H2-Ab1, Cd86, or Cd80. In some aspects, the tissue can be aorta, adipose tissue (white and brown), liver, lung, and circulating monocytes, or tissue macrophages. In any of the methods disclosed herein, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or a combination thereof can increase one or more anti-inflammatory markers in one or more macrophages. In some aspects, the one or more anti-inflammatory markers can be IL-10, Arg1, Retnla, and Chil3. In any of the methods disclosed herein, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or a combination thereof can increase mitochondrial activity in one or more macrophages or blood monocytes. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or a combination thereof can increase mitochondrial activity in hematopoietic stem cells or progenitor cells of the one or more macrophages or blood monocytes. Disclosed herein are methods of treating or ameliorating a symptom of a cardiometabolic disease in a subject. In some aspects, the cardiometabolic disease can be clinical complications of type II diabetes, including but not limited to hyperglycemia and atherosclerosis cardiovascular disease resulting in myocardial infarction and stroke. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the administration of the therapeutically effective amount of the miR- 146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase expression of one or more anti-inflammatory cytokines. In some aspects, the one or more anti- inflammatory cytokine can be IL-10 or adiponectin. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase one or more M2-associated markers. In some aspects, the one or more M2-associated markers can be Arg1, Retnla, or Chil3. Cardiometabolic disease is a constellation of various metabolic syndromes that predominantly include obesity, hyperlipidemia, insulin resistance, type II diabetes, fatty liver diseases, and atherosclerosis. The major cause of death in cardiometabolic disease is the development of coronary artery disease that predisposes patients to myocardial infarctions. Disclosed herein are methods of treating or ameliorating a symptom of an acute or a chronic inflammatory disorder in a subject. In some aspects, the chronic inflammatory disorder can be obesity, hyperlipidemia, insulin resistance, type II diabetes, fatty liver diseases, or atherosclerosis. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase expression of one or more anti-inflammatory cytokines. In some aspects, the one or more anti-inflammatory cytokine can be IL-10 or adiponectin. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase one or more M2-associated markers. In some aspects, the one or more M2-associated markers can be Arg1, Retnla, or Chil3. The major cause of death in cardiometabolic disease is the development of coronary artery disease that predisposes patients to myocardial infarctions and stroke. In some aspects, the acute inflammatory disorder can be acute sepsis. Acute sepsis can that result from an overstimulation of NF-kB and glycolytic metabolism that could be attenuated and controlled by administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142a antagonist, or a combination thereof. In some aspects, the step of administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142a antagonist, or a combination thereof can reduce glycolysis and increase oxidative phosphorylation in the mitochondria of innate immune cells including but not limited to monocytes and neutrophils. Disclosed herein are methods of ameliorating a symptom of atherosclerosis in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the administration of the therapeutically effective amount of the miR- 146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase expression of one or more anti-inflammatory cytokines. In some aspects, the one or more anti- inflammatory cytokine can be IL-10 or adiponectin. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase one or more M2-associated markers. In some aspects, the one or more M2-associated markers can be Arg1, Retnla, or Chil3. Atherosclerosis is the build of plaque in the intimal layer of arterial blood vessels. This buildup of plaque may eventually rupture, causing local thrombosis that prevents blood flow. Major symptoms and manifestations of atherosclerosis include peripheral arterial disease, which can lead to critical limb ischemia, coronary arterial disease, which can lead to myocardial infarction, and ischemic stroke. Disclosed herein are methods of enhancing fatty acid oxidation and/or oxidative phosphorylation in a cell of a subject in a subject. In some aspects, the methods can comprise administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof. In some aspects, the cell can be an immune cell, a hematopoietic stem cell or a progenitor cell. In some aspects, the cell can an adipocyte or a macrophage. In some aspects the cell can be an adipocyte or a macrophage in fat tissue. In some aspects, wherein the cell can be a hepatocyte or a macrophage. In some aspects, wherein the cell can be a hepatocyte or a macrophage in liver tissue. In some aspects, wherein the cell can be a cardiomyocyte, fibroblast or a macrophage in the heart. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase expression of one or more anti-inflammatory cytokines. In some aspects, the one or more anti-inflammatory cytokine can be IL-10 or adiponectin. In some aspects, the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can increase one or more M2- associated markers. In some aspects, the one or more M2-associated markers can be Arg1, Retnla, or Chil3. In some aspects, oxidative phosphorylation can be increased in one or more adipocytes. The increase in oxidative phosphorylation can maintain metabolic homeostasis. For example, an increase in oxidative phosphorylation can improve the cells capacity to utilize biofuels such as lipids, preventing an accumulation of lipids in cells. In some aspects, increased oxidative phosphorylation can also reduce the process of glycolysis and the excessive use of glucose for energy production thereby reducing the levels of reactive oxygen radicals produced in the cell that are recognized to cause cellular stress, senescence and premature cellular death. In some aspects, methods can increase mitochondrial activity in the adipocytes. Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). There are both pro-inflammatory cytokines and anti-inflammatory cytokines. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and are related to the development of contralateral hyperalgesia/allodynia. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF). In some aspects, the subject in need of treatment has been diagnosed with hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease. In some aspects, the subject in need of treatment has been diagnosed with hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease prior to the administering step. In some aspects, the miR-146a agonist or mimic can be hsa-miR-146a-5p. In some aspects, the hsa miR-146-5p can comprise the nucleotide sequence UGAGAACUGAAUUCCAUGGGUU (SEQ ID NO: 1). In some aspects, the hsa miR-146-5p can comprise the nucleotide sequence GAGAACU (SEQ ID NO: 4). In some aspects, the composition can comprise a sequence derived from miR-584-5p. In some aspects, the methods described herein can include the administration of miR- 146-5p or variants thereof. Variants can include nucleotide sequences that are substantially similar to sequences of miR-146-5p, precursors or sequences derived thereof. In some aspects, variants include nucleotide sequences that are substantially similar to the miR-146-5p sequence or fragments thereof, including the miR-146-5p seed sequence. Variants can also include nucleotide sequences that are substantially similar to sequences of miRNA disclosed herein. A “variant” can mean a difference in some way from the reference sequence other than just a simple deletion of an N- and/or C-terminal nucleotide. Variants can also or alternatively include at least one substitution and/or at least one addition, there may also be at least one deletion. In some aspects, the variant miRNA to be administered can comprise a sequence displaying at least 80% sequence identity to the sequence of miR-146-5p (SEQ ID NOs: 1, 2, or 3). In some aspects, the miRNA to be administered can comprise a sequence displaying at least 90% sequence identity to SEQ ID NOs: 1, 2, or 3. In some aspects, the miRNA to be administered can comprise a sequence displaying at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 1, 2, or 3. Alternatively or in addition, variants can comprise modifications, such as non-natural residues at one or more positions with respect to the miR-146-5p sequence. In some aspects, the variant can be a sequence wherein the last nucleotide of the miRNA is changed. In some aspects, the variant can be a sequence comprising at least one or at least two substitutions at the 5’ end of the miR-146-5p. In an aspect, nucleotide substitutions can include nucleotide substitutions to the reference sequence which increase stability of the miR-146-5p or a variant thereof. In some aspects, nucleotide substitutions can be those which permit conjugation of the miR-146-5p or a variant thereof to a polymer or copolymer for forming a nanoparticle. Nucleotide substitutions can be substitutions of one or two bases. Deletions and insertions can include from one (1) to about seven (7) bases. Substitutions, deletions, insertions or any combination thereof may be used to arrive at a final derivative or variant. Generally these changes are done on a few nucleotides to minimize the alteration of the molecule. However, larger changes may be tolerated in certain circumstances. Generally, the nucleotide identity between individual variant sequences can be at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. Thus, a “variant sequence” can be one with the specified identity to the parent or reference sequence of the invention, and shares biological function, including, but not limited to, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the specificity and/or activity of the parent sequence. For example, a “variant sequence” can be a sequence that contains 1, 2, 3 or 4 nucleotide base changes as compared to the parent or reference sequence of the invention, and shares or improves biological function, specificity and/or activity of the parent sequence. In some aspects, the parent or reference sequence can be miR-146-5p. In some aspects, any of sequences disclosed herein can include a single nucleotide change as compared to the parent or reference sequence. In some aspects, any of the sequences disclosed herein can include at least two nucleotide changes as compared to the parent or reference sequence. The nucleotide identity between individual variant sequences can be at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. Thus, a “variant sequence” can be one with the specified identity to the parent sequence of the invention, and shares biological function, including, but not limited to, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the specificity and/or activity of the parent sequence. The variant sequence can also share at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the specificity and/or activity of the parent sequence. The compositions described herein can be formulated to include a therapeutically effective amount of miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof, or a variant thereof described herein. Therapeutic administration encompasses prophylactic applications. Based on genetic testing and other prognostic methods, a physician in consultation with their patient can choose a prophylactic administration where the patient has a clinically determined predisposition or increased susceptibility (in some cases, a greatly increased susceptibility) to cardiometabolic inflammation, atherosclerosis, or cardiac failure. The compositions described herein can be formulation in a variety of combinations. The compositions described herein can be administered to the subject (e.g., a human patient) in an amount sufficient to delay, reduce, or preferably prevent the onset of clinical disease. Accordingly, in some aspects, the patient can be a human patient. In therapeutic applications, compositions are administered to a subject (e.g., a human patient) already with or diagnosed with cardiometabolic inflammation, atherosclerosis, cardiac failure, hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease in an amount sufficient to at least partially improve a sign or symptom or to inhibit the progression of (and preferably arrest) the symptoms of the condition, its complications, and consequences. An amount adequate to accomplish this is defined as a “therapeutically effective amount.” A therapeutically effective amount of a composition (e.g., a pharmaceutical composition) can be an amount that achieves a cure, but that outcome is only one among several that can be achieved. As noted, a therapeutically effective amount includes amounts that provide a treatment in which the onset or progression of the cardiometabolic inflammation, atherosclerosis, cardiac failure, hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease is delayed, hindered, or prevented, or the cancer or a symptom of the cardiometabolic inflammation, atherosclerosis, cardiac failure, hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease is ameliorated. One or more of the symptoms can be less severe. Recovery can be accelerated in an individual who has been treated. The duration of treatment with any composition provided herein can be any length of time from as short as one day to as long as the life span of the host (e.g., many years). For example, the compositions can be administered once a week (for, for example, 4 weeks to many months or years); once a month (for, for example, three to twelve months or for many years); or once a year for a period of 5 years, ten years, or longer. It is also noted that the frequency of treatment can be variable. For example, the present compositions can be administered once (or twice, three times, etc.) daily, weekly, monthly, or yearly. Compositions comprising a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof can be administered to a subject in a dose or doses of about or of at least about 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1500, 2000, 2500, 3000 μg or mg, or any range between 0.5 μg or mg and 3000 μg or mg. The amount specified can be the amount administered as the average daily, average weekly, or average monthly dose, or it may be expressed in terms of mg/kg, where kg refers to the weight of the patient and the mg is specified above. In other embodiments, the amount specified is any number discussed above but expressed as mg/m². A clinician can readily determine the effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof —i.e. the amount of miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof, or a fragment or a variant thereof needed to treat or suppress inflammation caused by hyperlipidemia, increase plasma IL-10 levels, enhance fatty acid oxidation and oxidative phosphorylation, decrease hematopoiesis, decrease myelopoiesis, decrease aortic leukocyte accumulation, or suppress glycolysis and/or oxidative stress in immune cells in subjects in need thereof, by taking into account factors, such as the size and weight of the subject; the extent of disease penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic. The total effective amount of the compositions as disclosed herein can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol in which multiple doses are administered over a more prolonged period of time. Alternatively, continuous intravenous infusions sufficient to maintain therapeutically effective concentrations in the blood are also within the scope of the present disclosure. The compositions described herein can be administered in conjunction with other therapeutic modalities to a subject in need of therapy. The miR-146a agonist or mimic, the miR- 142 antagonist, or the combination thereof, or the fragment or variant thereof can be given prior to, simultaneously with or after treatment with other agents or regimes. For example, the miR- 146a agonist or mimic, the miR-142 antagonist, or the combination thereof, or the fragment or variant thereof alone can be administered in conjunction with standard therapies used to treat cardiometabolic inflammation, atherosclerosis, and cardiac failure or hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease. In some aspects, the miR-146a agonist or mimic and the miR-142 antagonist can be co- formulated. The compositions described herein can be formulated to include a therapeutically effective amount of the miR-146a agonist or mimic in combination with the miR-142 antagonist disclosed herein. In some aspects, the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof can be contained within a pharmaceutical formulation. In some aspects, the pharmaceutical formulation can be a unit dosage formulation. The miR-146a agonist or mimic, the miR-142 antagonist, or a combination thereafter can be administered as “combination” therapy. It is to be understood that, for example, miR-584-5p, or a variant thereof can be provided to the subject in need, either prior to administration of IL-4 macrophage exosomes, anti-inflammatory biologics (e.g., anti-IL1b agents, anti-TNF agents) or any combination thereof, concomitant with administration of IL-4 macrophage exosomes, anti- inflammatory biologics (e.g., anti-IL1b agents, anti-TNF agents) or any combination thereof (co- administration) or shortly thereafter. A^{RTICLES OF} M^ANUFACTURE The composition described herein can be packaged in a suitable container labeled, for example, for use as a therapy to treat cardiometabolic inflammation, atherosclerosis, and cardiac failure or hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease or any of the methods disclosed herein. Accordingly, packaged products (e.g., sterile containers containing the composition described herein and packaged for storage, shipment, or sale at concentrated or ready-to-use concentrations) and kits, including at least miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof as described herein and instructions for use, are also within the scope of the disclosure. A product can include a container (e.g., a vial, jar, bottle, bag, or the like) containing the composition described herein. In addition, an article of manufacture further may include, for example, packaging materials, instructions for use, syringes, buffers or other control reagents for treating or monitoring the condition for which prophylaxis or treatment is required. The product may also include a legend (e.g., a printed label or insert or other medium describing the product's use (e.g., an audio- or videotape)). The legend can be associated with the container (e.g., affixed to the container) and can describe the manner in which the compound therein should be administered (e.g., the frequency and route of administration), indications therefor, and other uses. The compounds can be ready for administration (e.g., present in dose-appropriate units), and may include a pharmaceutically acceptable adjuvant, carrier or other diluent. Alternatively, the compounds can be provided in a concentrated form with a diluent and instructions for dilution. In some aspects, the kits can include one or more of miR-146a agonist or mimic, a miR- 142 antagonist, or a combination thereof or molecules derived from miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof; expression vectors comprising nucleic acid sequences encoding miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof or one or more molecules derived from miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof; reagents for preparing samples from blood samples or biopsy samples. The kit can include one or more pharmaceutically acceptable carriers. In addition, devices or materials for administration of the miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof (e.g., syringes (pre-filled with miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof), needles, liposomes, etc.) can also be included. Examples Example 1: Apolipoprotein E suppresses hyperlipidemia-driven hematopoiesis, inflammation, and atherosclerosis by controlling mitochondrial metabolism Apolipoprotein E (ApoE) is recognized for its pleiotropic properties that suppress inflammation. The results described herein show that ApoE serves as a metabolic rheostat that regulates microRNA-control of glycolytic and mitochondrial activity in myeloid cells and hematopoietic stem and progenitor cells (HSPCs). ApoE expression in Apoe^-/- myeloid cells increases microRNA-146a that reduces NF-κB ^driven GLUT1 expression and glycolytic activity. In contrast, ApoE expression reduces microRNA-142a that increases CPT1A, fatty acid oxidation, and oxidative phosphorylation. Improved mitochondrial metabolism by ApoE expression causes an enrichment of TCA cycle metabolites and NAD⁺ in macrophages. The study of mice with conditional ApoE expression supports the capacity for ApoE expression to foster microRNA-controlled immunometabolism. Modulation of microRNA-146a and -142a in the hematopoietic system of hyperlipidemic mice using RNA mimics and antagonists improves mitochondrial metabolism that suppresses inflammation and hematopoiesis. The findings provide evidence of an RNA regulatory network controlled by ApoE expression that exerts a metabolic control of hematopoiesis and inflammation in hyperlipidemia. ApoE suppresses glycolytic metabolism in myeloid cells by controlling GLUT1-mediated glucose uptake via miR-146a regulation of NF-κB signaling. To explore whether ApoE exerts a control over bioenergetic activity in myeloid cells, ApoE was examined for its ability to modulate glycolytic metabolism. For this, it was tested whether a loss of ApoE in bone marrow- derived macrophages (BMDM) derived from Apoe^-/- mice altered both basal and LPS-stimulated aerobic glycolysis using a Seahorse Glycolytic Rate Assay to measure the glycolytic proton efflux rate (glycoPER). As shown in FIGS.1A and 1B, Apoe^-/- BMDM displayed elevated levels of basal and compensatory glycolysis, as well as an increased percentage of total proton efflux rate (PER) produced from glycolytic activity (% PER from Glycolysis) as compared to Apoe^+/+ BMDM. Interestingly, BMDM derived from mice deficient in one ApoE allele (Apoe^+/-) exerted a modest but significant increase in glycolysis under both basal and LPS-stimulated conditions (FIGS.1A and 1B). In seeking to uncover mechanisms to explain these observations, it was tested whether the prior report documenting a role for ApoE in raising miR-146a levels (Li K, et al. Circ Res. 2015;117(1):e1-e11) could contribute to its capacity to suppress glycolytic metabolism. Consistent with the prior study, it was found that miR-146a levels are expressed in an ApoE gene-dose dependent manner, with Apoe^+/+ BMDM expressing the highest levels of miR-146a, followed by Apoe^+/- BMDM and Apoe^-/- BMDM (FIG.1C). It was also observed that bone marrow derived dendritic cells (BMDC) express ApoE at similar levels as BMDM (FIG.8A). As with BMDM, a dose-dependent effect of miR-146a levels was observed in BMDC that lacked either one or both ApoE alleles (FIG.1C). Next, it was tested whether an ectopic expression of ApoE in Apoe^-/- macrophages and dendritic cells could normalize miR-146a levels. This was done by transfecting Apoe^-/- BMDM and BMDC with an ApoE expression vector (100 ng/mL) that caused a 2-fold and 1.7-fold increase in ApoE mRNA and protein production relative to WT cells (FIGS.8B-C). Importantly, restoration of ApoE mRNA expression in Apoe- ^/- BMDM and BMDC normalized levels of miR-146a by raising them more than 2-fold in both forms of myeloid cells (FIG.1D). Next, it was examined whether increased expressions of miR-146a could alter cellular bioenergetic activity via its mRNA targets. Findings shown in FIGS.8D-E confirm an expected downregulation of canonical miR-146a targets Traf6 & Irak1, two central mediators of NF-κB signaling (Li K, et al. Circ Res.2015;117(1):e1-e11; Taganov KD, et al. Proc Natl Acad Sci U S A.2006;103(33):12481-6; and Boldin MP, et al. J Exp Med.2011;208(6):1189-201), in Apoe^+/+ BMDM/BMDC and Apoe^-/- BMDM/BMDC transfected with an ApoE expression vector. It was also observed reduced nuclear accumulation of phosphorylated NF-κB p65 subunit in Apoe^+/+ BMDM and Apoe^-/- BMDM transfected with an ApoE expression vector (FIG.8F). Furthermore, increased Traf6 and Irak1 mRNA levels were detected in Apoe^+/+ BMDM transfected with a miR-146a anti-sense oligonucleotide (miR-146a inhib) (FIG.8G). Together, these data support a role for ApoE expression in controlling myeloid NF-κB activity via an upregulation of miR- 146a (Li K, et al. Circ Res.2015;117(1):e1-e11). Next, it was tested whether an ApoE/NF-κB axis contributes to the control of cellular glycolytic activity. To this end, the levels of GLUT1-mediated glucose uptake and glycolytic functions that are documented to be upregulated by NF-κB activity (Wang X, et al. Mol Cell. 2019;76(1):148-62 e7; and Obaid M, et al. Sci Rep.2021;11(1):232) were assessed and confirmed by the data in FIGS.1E and 1F. These findings show that Apoe^-/- BMDM/BMDC expressed greater levels of GLUT1 mRNA (Slc2a1) than Apoe^+/+ cells when stimulated with lipopolysaccharides (LPS), a model for Toll-like receptor signaling (Medzhitov R, et al. Nature. 1997;388(6640):394-7; and Poltorak A, et al. Science.1998;282(5396):2085-8), while Apoe^+/- BMDM/BMDC expressed intermediate expression levels of the gene (FIG.1G). Consistently, LPS-stimulated Apoe^-/- BMDM displayed the greatest protein cell surface density of GLUT1 (FIG.1H). Such elevated levels of cell surface GLUT1 in LPS-stimulated Apoe^-/- BMDM led to enhanced glucose uptake (FIG.1I), and production of lactate (FIG.1J), the end-product of aerobic glycolysis (Kelly B, and O'Neill LA. Cell Res.2015;25(7):771-84). In line with a role for ApoE in controlling glycolysis, these findings show that an ectopic expression of ApoE in Apoe^-/- BMDM decreased LPS-stimulated GLUT1 expression, glucose uptake, and lactate production (FIGS.1K-N). The anti-glycolytic property of ApoE expression was confirmed to be dependent on miR-146a as inhibiting this microRNA in Apoe^+/+ BMDM markedly upregulated these metabolic processes (FIGS. S1H-K). Taken together, these data bring to light a previously unrecognized role of ApoE in controlling NF-κB-driven glucose uptake and glycolytic activity in myeloid cells through its capacity to upregulate miR-146a. ApoE enhances fatty acid oxidation and oxidative phosphorylation in myeloid cells by upregulating CPT1-alpha via its control of miR-142a. In light of these findings documenting a capacity for ApoE to suppress glycolytic activity, it was next examined whether it had an ability to upregulate oxidative phosphorylation (OxPHOS). To test this outcome, the oxygen consumption rate (OCR) was measured in Apoe^+/+ and Apoe^-/- BMDM under basal and LPS- stimulated conditions using the Seahorse Mito Stress Assay. The data show that unstimulated Apoe^+/+ BMDM displayed enhanced OxPHOS as detected by elevated basal and maximal respiration associated with a higher proton leak and ATP production compared to unstimulated Apoe^-/- BMDM (FIGS.2A and 2B). While LPS-stimulation caused a profound reduction in OxPHOS in both cell types, Apoe^+/+ BMDM retained more robust basal respiration and ATP production relative to Apoe^-/- BMDM (FIGS.2A and 2B). Consistent with the observations of a dose-dependent effect in ApoE-controlled glycolytic function (FIG.1), the loss of one ApoE allele caused Apoe^+/- BMDM to display an intermediate impairment of OxPHOS under basal conditions and following LPS-stimulation (FIGS.2A and 2B). To further document the metabolic rheostat properties of ApoE, mitochondrial activity was measured in BMDM and BMDC derived from Apoe^+/+ and Apoe^-/- mice. In doing so, a 30% increase in mitochondrial membrane potential (ΔΨm) was observed in myeloid cells derived from Apoe^+/+ mice (FIG.2C). Furthermore, an ectopic expression of ApoE in Apoe^-/- BMDM/BMDC robustly increased mitochondrial ΔΨm levels (FIG.9A). Together these findings support cellular ApoE expression as a driver of mitochondrial activity in myeloid cells Building on the finding linking ApoE expression to miR-146a regulation of NF-κB- driven inflammatory signaling and glycolytic activity shown in FIG.1, it was tested whether other microRNAs sensitive to ApoE could explain the observations of improved OxPHOS activity in Apoe^+/+ BMDM. Unbiased sequencing of RNA isolated from cultured Apoe^+/+ and Apoe^-/- BMDM was performed. Data from FIG.9B revealed 78 microRNAs that were differentially expressed between Apoe^+/+ and Apoe^-/- BMDM. Among these, miR-146a was confirmed to be more abundant in Apoe^+/+ than in Apoe^-/- BMDM (FIG.9B), supporting the findings in FIG.1C and prior study (Li K, et al. Circ Res.2015;117(1):e1-e11). Interestingly, miR-142a, recognized to be an important modulator of immunometabolism in myeloid cells (Sun Y, et al. J Clin Invest.2019;129(5):2029-42), was also identified to be significantly downregulated in Apoe^+/+ versus Apoe^-/- BMDM (FIG.9B), a finding that was confirmed by qRT-PCR analyses (FIG.2D). This pattern of altered miR-142a expression was subsequently confirmed in BMDC derived from the two strains of mice (FIG.2D), and an intermediate expression of this microRNA was detected in Apoe^+/- BMDM/BMDC (FIG.2D). Importantly, an ectopic expression of ApoE in Apoe^-/- BMDM/BMDC transfected with 100 ng/mL of an ApoE expression vector caused a 2-fold reduction in miR-142a levels (FIG.2E). These findings show that ApoE expression substantially impacts microRNA diversity in myeloid cells. In seeking to uncover how ApoE improved OxPHOS via its control of miR-142a, mRNA Cpt1a, encoding carnitine palmitoyltransferase-1a (CPT1A), a component of the carnitine shuttle that serves as a rate-limiting enzyme for mitochondrial fatty acid oxidation (FAO) and OxPHOS (Sun Y, et al. J Clin Invest.2019;129(5):2029-42) was targeted. To this end, it was tested whether an upregulation of miR-142a in the absence of ApoE expression would reduce Cpt1a/CPT1A expression in macrophages and dendritic cells. In line with this reasoning, the data shown in FIGS.2F and 10A demonstrate that Apoe^-/- BMDM/BMDC displayed a 4-fold and 2.5-fold reduction in Cpt1a mRNA levels at basal levels and when stimulated with LPS, respectively, as compared to Apoe^+/+ BMDM/BMDC. Furthermore, intermediate expression of this mRNA was detected in Apoe^+/- BMDM, supporting a dose-dependent effect for ApoE expression-controlled Cpt1a mRNA levels (FIG.2F). Importantly, the functional impact of Cpt1a mRNA modulation by ApoE expression was revealed by a 2-fold reduction in CPT1A protein levels in unstimulated Apoe^-/- BMDM/BMDC as compared to Apoe^+/+ cells (FIGS.2G-H and 10B-C). Remarkably, an ectopic expression of ApoE in Apoe^-/- BMDM/BMDC increased Cpt1a levels by 6- and 3.5-fold of those seen at basal levels and when stimulated with LPS, respectively, as compared to control cells and cells transfected with an empty vector (FIG.10D). This increase in Cpt1a mRNA levels parallel the observed 3.5-fold and 2-fold increase in CPT1A protein levels in unstimulated Apoe^-/- BMDM and BMDC transfected with an ApoE expression vector, respectively (FIGS.2I-J and 10B-C). Next, it was tested whether inhibiting miR-142a in Apoe^-/- BMDM using an anti-sense oligonucleotide (miR-142 inhibitor) would restore expression levels of CPT1A in these cells. The data show that when transfected with miR-142 inhib, Apoe^-/- BMDM displayed a 2.2-fold and 1.8-fold increase in Cpt1a mRNA levels at basal levels and when stimulated with LPS, respectively, as compared to cells transfected with negative control oligonucleotides or non-transfected cells (FIG.2K). Such elevated levels of Cpt1a mRNA paralleled an observed 1.7-fold increase in CPT1A protein levels in Apoe^-/- BMDM transfected with miR-142 inhibitor (FIGS.2L and 2M). To address the translational relevance of these findings, it was assessed whether targeting miR-142a could also raise CPT1A levels in human THP-1 macrophages. The findings shown in FIGS.10E and F reveal that this led to an increase in Cpt1a mRNA and protein levels (CPT1A). Together, the data identify miR- 142a as a microRNA regulated by ApoE expression that in this case serves to modulate the expression of CPT1A. Stemming from the data shown in FIGS.2F-M that support a role for ApoE in fostering CPT1A expression, it was tested whether levels of OCR were associated with CPT1A-mediated mitochondrial FAO by treating Apoe^+/+ and Apoe^-/- BMDM with the CPT1A inhibitor etomoxir. Etomoxir was used at a working concentration of 4 µM and is known to specifically target CPT1A activity without causing cellular oxidative stress that occurs when the compound is used at concentrations greater than 5 µM (O'Connor RS, et al. Sci Rep.2018;8(1):6289). Data shown in FIGS.2N-O reveal that, despite a higher OCR at basal state, unstimulated Apoe^+/+ BMDM display a more substantial reduction in their OCR upon etomoxir treatment as compared to Apoe^-/- BMDM, indicating that constitutively elevated OxPHOS in Apoe^+/+ BMDM is largely driven by CPT1A-dependent FAO. Furthermore, it was observed that LPS-stimulated Apoe^+/+ and Apoe^-/- BMDM similarly displayed minor reductions in OCR upon etomoxir treatment as compared to unstimulated cells, with Apoe^+/+ BMDM displaying a more pronounced drop as compared to Apoe^-/- BMDM (FIGS.2N and O). Importantly, Apoe^-/- BMDM transfected with miR-142a inhibitor also displayed 40% greater ΔΨm as compared to non-transfected or negative control-transfected cells (FIG.2P). To further document a role for ApoE in fostering mitochondrial activity in myeloid cells via a miR-142a/CPT1A axis, neutral lipid levels were measured in cultured BMDM and BMDC. Data shown in FIG.10G reveal a 30% decrease in neutral lipids in both Apoe^+/+ BMDM and BMDC as compared to Apoe^-/- cells. This observation was recapitulated in Apoe^-/- BMDM/BMDC transfected either with an ApoE expression vector (FIG.10H), or with miR- 142a inhibitor (FIG.10I). Together, these data uncover a role for ApoE expression in rewiring myeloid cell metabolism by suppressing levels of miR-142a that upregulates FAO and OxPHOS. To validate the findings pointing to ApoE-control of bioenergetic metabolism in myeloid cells, an unbiased metabolomics analysis of Apoe^+/+ and Apoe^-/- BMDM was performed. Doing so identified altered levels of metabolites central to glycolytic metabolism and OxPHOS. Findings shown in FIG.2Q reveal significant differences in the levels of 40 metabolites between both groups of cells (FDR < 0.05). Consistent with the bioenergetic data shown in FIGS.2A-B and 2N-O, results of this assay revealed an accumulation of numerous metabolites associated with OxPHOS in Apoe^+/+ BMDM. Most notably included are those associated with the TCA cycle (citrate, succinyl-CoA, and malic acid), glutaminolysis (glutamate), and glycine metabolism (dimethylglycine), as well as NAD⁺ that were each highly enriched in extracts of Apoe^+/+ BMDM as compared to those of Apoe^-/- BMDM (FIG.2Q). These data were compared to extracts collected from Apoe^+/+ BMDM at a resting state and when stimulated with interleukin-4 to simulate models of M0 and M2 macrophages, respectively. When comparing these data, it was noted that 15 metabolites found to be highly enriched in Apoe^+/+ BMDM versus Apoe^-/- BMDM, were similarly enriched in M2-like BMDM (FIGS.2Q and 11). Taken together, these data provide compelling evidence supporting a role for ApoE in regulating immunometabolism by maintaining myeloid cell bioenergetic activity skewed towards OxPHOS, a metabolic process recognized for dampening inflammatory responses in macrophages (Kelly B, and O'Neill LA. Cell Res.2015;25(7):771-84) and to promote the resolution of inflammation in atherosclerosis (Koelwyn GJ, et al. Nat Immunol.2018;19(6):526-37; and Tabas I and Bornfeldt KE. Circ Res. 2020;126(9):1209-27). ApoE controls the miR-146a/NF-κB/GLUT1 & miR-142a/CPT1A signaling axes in myeloid cells of hyperlipidemic mice. To test the physiological relevance of the in vitro data derived from the study of BMDM and BMDC, it was tested whether ApoE expression could control bioenergetic activities in primary myeloid cells of hyperlipidemic mice. To address this question, the hypomorphic ApoE (Apoe^h/h) mouse model of reduced Apoe gene expression, also termed HypoE mice (Raffai RL, and Weisgraber KH. J Biol Chem.2002;277(13):11064-8), was used to breed mice deficient in low density lipoprotein receptor expression (Ldlr^-/- mice). Reduced expression levels of the Apoe^h/h alleles in BMDM and peritoneal macrophages derived from Apoe^h/h Ldlr^-/- mice results in ApoE protein levels that are 2-5% of that of Wildtype (Apoe^+/+) mice (Gaudreault N, et al. PLoS One.2012;7(5):e35816), while macrophages derived from Apoe^-/- Ldlr^-/- mice showed no expression of ApoE as expected (FIG.12A). Data in FIG. 12B show that in spite of reduced ApoE expression in the cell types tested, Apoe^h/h Ldlr^-/- mice accumulated 4-fold more ApoE in the plasma than Wildtype (Apoe^+/+) mice due to impaired lipoprotein clearance mechanisms in the liver (Gaudreault N, et al. Arterioscler Thromb Vasc Biol.2012;32(2):264-72; and Eberle D, et al. Arterioscler Thromb Vasc Biol.2013;33(8):1759- 67). Importantly, chow-fed Apoe^h/h Ldlr^-/- mice displayed a similar accumulation of plasma cholesterol and triglycerides, and weight gain by 14 weeks of age as Apoe^-/- Ldlr^-/- mice (FIGS. 12C-E). Also consistent with prior studies using these mice (Gaudreault N, et al. Arterioscler Thromb Vasc Biol.2012;32(2):264-72), it was observed an accumulation of ApoE in Apoe^h/h Ldlr^-/- mouse plasma that altered their lipoprotein cholesterol profile as compared to that of Apoe^-/- Ldlr^-/- mice. Specifically, an accumulation of ApoE in hyperlipidemic plasma lowered VLDL-cholesterol level while increasing levels of cholesterol associated with IDL/LDL as well as HDL lipoproteins (FIG.12F). Thus, while both mouse models accumulated similar levels of cholesterol and triglycerides in plasma, ApoE altered their distribution among lipoprotein classes. Next, it was tested whether sub-physiological expression of ApoE in peritoneal macrophages of Apoe^h/h Ldlr^-/- mice could alter their miRNA repertoire including miR-146a and miR-142a as it was observed with the study of cultured Apoe^+/+ cells. Data shown in FIGS.3A and 13A demonstrate that peritoneal macrophages and splenic CD11c⁺ cells collected from Apoe^h/h Ldlr^-/- mice displayed 2-fold more miR-146a levels than cells collected from Apoe^-/- Ldlr- ^/- mice, a finding consistent with the previous study of monocytes and macrophages derived from these mice (Li K, et al. Circ Res.2015;117(1):e1-e11). Importantly, a 50% reduction in levels of miR-142a in myeloid cells collected from Apoe^h/h Ldlr^-/- mice as compared to those collected from Apoe^-/- Ldlr^-/- mice was also found (FIGS.3A and 13A). Next, it was examined whether the altered microRNA expression pattern in myeloid cells derived from these hyperlipidemic mouse models also resulted in altered gene expression and bioenergetic activities as it was observed in cultured BMDM and BMDC derived from Apoe^+/+ and Apoe^-/- mice (FIGS.1A-B, 1E, 2A-B, 2F, 8D-G, and 10A-D). Consistent with the prior findings in this mouse model (Li K, et al. Circ Res. 2015;117(1):e1-e11), the data in FIGS.14B and C demonstrate a downregulation of miR-146a target genes Traf6 & Irak1, two functional mediators of NF-κB signaling (Taganov KD, et al. Proc Natl Acad Sci U S A.2006;103(33):12481-6; and Boldin MP, et al. J Exp Med. 2011;208(6):1189-201) in peritoneal macrophages and splenic CD11c⁺ cells of Apoe^h/h Ldlr^-/- mice. Furthermore, reduced nuclear accumulation of the phosphorylated NF-κB p65 subunit in peritoneal macrophages, splenic dendritic cells (MHCII⁺ CD11c⁺ cells), and blood monocytes (CD45⁺ CD11b⁺ CD115⁺ cells) isolated from Apoe^h/h Ldlr^-/- mice as compared to those from Apoe^-/- Ldlr^-/- mice was observed (FIG.13D). As NF-κB activity upregulates GLUT1-mediated glucose uptake and glycolytic metabolism (Obaid M, et al. Sci Rep.2021;11(1):232), it was next examined whether the expression of ApoE in peritoneal macrophages derived from hyperlipidemic mice also impacted these processes via the upregulation of miR-146a as observed in cultured BMDM and BMDC of Apoe^+/+ and Apoe^-/- mice. In line with this reasoning, reduced levels of GLUT1 mRNA (Slc2a1) was detected in peritoneal macrophages and splenic CD11c⁺ cells derived from Apoe^h/h Ldlr^-/- mice cultured in an unstimulated or LPS-stimulated condition as compared to those examined from Apoe^-/- Ldlr^-/- mice (FIGS.3B and 13E). The reduction in Slc2a1 levels also paralleled an observed reduction in GLUT1⁺ cells and GLUT1 protein density on the surface of peritoneal macrophages upon LPS-stimulation (FIGS.3C and 13F). Such reduced levels of GLUT1 in peritoneal macrophages derived from Apoe^h/h Ldlr^-/- mice led to a reduction in glucose uptake by the cells under both unstimulated or LPS-stimulated conditions (FIG.3D). Furthermore, a reduced accumulation of lactate was observed in the conditioned media of these cells upon LPS- stimulation (FIG.3E), a hallmark for detecting aerobic glycolysis driven by LPS-stimulation (Kelly B, and O'Neill LA. Cell Res.2015;25(7):771-84). NF-κB-driven glucose uptake was measured in macrophages following LPS stimulation. Data in FIGS.3F and 13G demonstrate a normalization of Slc2a1 mRNA expression levels and glucose uptake in LPS-stimulated peritoneal Apoe^-/- Ldlr^-/- mouse macrophages when pre-treated with the NF-κB inhibitor BAY11- 7085. Having confirmed the existence of an ApoE/miR146a axis in controlling glycolytic metabolism in myeloid cells of hyperlipidemic mice, it was tested whether an ApoE/miR-142a axis was also active in controlling OxPHOS in these cells. In line with in vitro data shown in FIG.2F, peritoneal macrophages collected from Apoe^h/h Ldlr^-/- mice and tested under control or LPS-stimulated conditions displayed a 2-fold and 1.6-fold increase in levels of Cpt1a mRNA, respectively, relative to cells collected from hyperlipidemic Apoe^-/- Ldlr^-/- mice (FIG.3G). Increased levels of Cpt1a mRNA in splenic CD11c⁺ cells derived from Apoe^h/h Ldlr^-/- mice were similarly detected when cultured in control or LPS-stimulated conditions (FIG.13H). Such ApoE-driven Cpt1a mRNA increase was corroborated with a 60% increase in CPT1A protein levels detected in extracts of peritoneal macrophages and splenic CD11c⁺ cells collected from Apoe^h/h Ldlr^-/- mice and Apoe^-/- Ldlr^-/- mice, respectively (FIGS.3H-I and 13I-J). Together, these studies of primary myeloid cells derived from these models of hyperlipidemic mice support a scenario where cellular ApoE expression, albeit at reduced levels seen in Apoe^h/h Ldlr^-/- mice, drives two microRNA-controlled axes, namely miR-146a/NF-κB/GLUT1 and miR124a/CPT1A, recognized for their role in suppressing glycolysis and improving OxPHOS, respectively (Sun Y, et al. J Clin Invest.2019;129(5):2029-42; and Runtsch MC, et al. PLoS Genet. 2019;15(2):e1007970). ApoE-regulation of miR-146a and miR-142a controls glycolytic and mitochondrial metabolism in myeloid cells of hyperlipidemic mice. Having established a role for ApoE expression in controlling levels of miR146a/142a and their target genes in primary myeloid cells of hyperlipidemic mice, it was next sought to test whether these signaling axes fostered bioenergetic activities. This was done by measuring OCR in peritoneal macrophages collected from Apoe^h/h Ldlr^-/- and Apoe^-/- Ldlr^-/- mice using the Seahorse Mito Stress Assay. Data shown in FIGS.3J-K revealed increased OxPHOS in peritoneal macrophages derived from Apoe^h/h Ldlr^-/- mice resulting in elevated basal and maximal respiration associated with a higher proton leak and ATP production. Consistent with these findings, peritoneal macrophages and splenic CD11c⁺ cells derived from Apoe^h/h Ldlr^-/- mice displayed 40% and 30% greater mitochondrial ΔΨm respectively as compared to cells derived from Apoe^-/- Ldlr^-/- mice (FIGS.3L and 13K-L). OCR associated with CPT1A-mediated mitochondrial FAO was measured by treating peritoneal macrophages collected from both mouse models with 4 μM of the selective CPT1A inhibitor, etomoxir. Data in FIGS.3M-N demonstrate that despite a higher OCR at basal state, Apoe^h/h Ldlr^-/- peritoneal macrophages displayed a more substantial drop in OCR upon etomoxir treatment as compared to cells derived from Apoe^-/- Ldlr^-/- mice. These data show that the elevated OxPHOS in Apoe^h/h Ldlr^-/- peritoneal macrophages is largely driven by CPT1A- dependent FAO. Consistent with prior findings in cultured BMDM and BMDC, reduced neutral lipid accumulation was also observed in Apoe^h/h Ldlr^-/- peritoneal macrophages and CD11c⁺ cells, revealed as a 40% reduction in LipidTOX fluorescent signal detected from these cells compared to controls (FIG.13M). In line with the in vitro data shown in FIGS.1A and B, cellular ApoE expression in Apoe^h/h Ldlr^-/- peritoneal macrophages also reduced glycolytic activity as revealed by lower levels of PER production associated with glycolysis as compared to peritoneal macrophages derived from Apoe^-/- Ldlr^-/- mice (FIGS.3O-P). Together, these data show that even sub-physiological ApoE expression is sufficient to potently control microRNA- regulated bioenergetic activity in myeloid cells collected from hyperlipidemic mice. Metabolic control by ApoE suppresses antigen presentation, co-stimulatory responses, and cytokine release in myeloid cells of hyperlipidemic mice. Altered metabolic states are recognized to impact the activation and inflammatory properties of myeloid cells and thereby atherosclerosis susceptibility (Koelwyn GJ, et al. Nat Immunol.2018;19(6):526-37; Tabas I, and Bornfeldt KE. Circ Res.2020;126(9):1209-27; and Kelly B, and O'Neill LA. Cell Res. 2015;25(7):771-84). Therefore, it was tested whether ApoE’s role in controlling microRNA- regulated bioenergetic pathways in myeloid cells impacts their inflammatory properties in hyperlipidemic mice. To address this question, levels of the cytokines TNF-α, IL-6, and IL-1β were measured in the conditioned media of LPS-stimulated splenic cells, bone marrow cells, and BMDM derived from Apoe^h/h Ldlr^-/- and Apoe^-/- Ldlr^-/- mice using a multiplex immunoassay. Data shown in FIG.3Q demonstrate that the three populations of LPS-stimulated cells derived from Apoe^h/h Ldlr^-/- mice secreted less inflammatory cytokines. These findings parallel the observed reduction in the gene expression levels of M1 macrophage markers and pro-inflammatory cytokines (H2-Ab1, Cd86, Cd80, Tnf, Il1b, Mcp1, and Il6) and increased M2-like macrophage markers (Arg1, Retnla, and Chil3) in primary peritoneal macrophages derived from Apoe^h/h Ldlr- ^/- and Apoe^-/- Ldlr^-/- mice (FIG.3R). It was next examined whether the expression of ApoE modulated inflammatory properties among populations of dendritic cell of hyperlipidemic mice. Data shown in FIGS. 14A-B show no significant differences in the numbers of splenic dendritic cells (total DC, Ly6C- MHCII⁺ CD11c⁺), conventional type 1 dendritic cells (cDC1, Ly6C- MHCII⁺ CD11c⁺ B220- CD11b- CD8a⁺), and conventional type 2 dendritic cells (cDC2, Ly6C- MHCII⁺ CD11c⁺ B220- CD11b⁺ CD8a-) between both mouse models when normalized by spleen weights. However, splenic plasmacytoid dendritic cells (plasmacytoid DC; Ly6C- MHCII⁺ CD11c⁺ B220⁺), recognized to promote atherosclerosis (Macritchie N, et al. Arterioscler Thromb Vasc Biol. 2012;32(11):2569-79; and Doring Y, et al. Circulation.2012;125(13):1673-83), were far less abundant in Apoe^h/h Ldlr^-/- mice as compared to Apoe^-/- Ldlr^-/- mice (FIGS.14A-B). Despite finding no differences in the numbers of total DC, cDC1, and cDC2 per spleen weight, reduced cell surface levels were observed of the major histocompatibility complex class II (MHC-II) among DC and cDC2, as well as plasmacytoid DC (FIGS.3S and 14C). Reduced cell surface levels of co-stimulatory molecules, CD86 and CD80, among total DC, cDC1, and cDC2 collected from the spleens of Apoe^h/h Ldlr^-/- mice were similarly detected as compared to those collected from Apoe^-/- Ldlr^-/- mouse spleens (FIGS.3S and 14C). Such altered expression patterns of MHC-II, CD86, and CD80 density across different subpopulations of DC in cells expressing ApoE corroborate with the reduced gene expression of H2-Ab1 (MHC-II gene), Cd86, and Cd80 mRNA detected in splenic CD11c⁺ cells derived from Apoe^h/h Ldlr^-/- mice (FIG. 14D). Furthermore, a reduction was observed in the mRNA levels of the cytokines Il12, Tnf, Il6, and Il1b in splenic CD11c⁺ cells derived from Apoe^h/h Ldlr^-/- mice as compared to those derived from Apoe^-/- Ldlr^-/- mice (FIG.14D). Taken together, these data reveal a role for ApoE in reducing chronic inflammation in hyperlipidemic mice by suppressing the inflammatory potential of myeloid cells. In line with in vivo data collected from the model of hyperlipidemic mice presented in FIGS.3Q-S and 16A-D, reduced inflammatory responses were recorded in cultured Apoe^+/+ BMDC and BMDM upon LPS-stimulation as compared to cells derived from Apoe^-/- cells. Data shown in FIG.14E reveal reduced cell surface levels of MHC-II, CD86, and CD80 in Apoe^+/+ BMDC. Substantially reduced levels of mRNA encoding these proteins (H2-Ab1, Cd86, and Cd80), as well as the pro-inflammatory cytokines (Il12, Tnf, Il6, and Il1b) in Apoe^+/+ BMDC upon LPS-stimulation was observed (FIG.14F). Reduced gene expression was similarly recorded for a panel of M1 macrophage markers and pro-inflammatory cytokines (Cd86, Cd80, Tnf, Il1b, Mcp1, and Il6) in Apoe^+/+ BMDM as compared to Apoe^-/- BMDM upon LPS- stimulation (FIG.14G). Based on these observations that support an immune-suppressive property of cell-derived ApoE expression in myeloid cell activation, it was next tested whether an ectopic expression of ApoE in Apoe^-/- BMDC and/or BMDM could suppress exaggerated inflammatory responses in Apoe^-/- myeloid cells upon LPS-stimulation. Data shown in FIG.14H reveal a 90%, 50%, and 60% reduction in H2-Ab1, Cd86, and Cd80 mRNA levels, respectively, in Apoe^-/- BMDC transfected with an ApoE expression vector as compared to non-transfected Apoe^-/- cells or cells transfected with an empty vector. Similarly, Apoe^-/- BMDM transfected with an ApoE expressing vector displayed a 40%, 50%, 50%, and 60% reduction in Tnf, Il1b, Il6, and Mcp1 mRNA levels, respectively (FIG.14H). ApoE control of microRNA-regulated bioenergetic metabolism suppresses hematopoiesis in hyperlipidemic mice. ApoE is recognized to control hyperlipidemia-driven hematopoiesis by blunting cytokine signaling in HSPC (Murphy AJ, et al. J Clin Invest.2011;121(10):4138-49). However, whether its impact on microRNA-regulated bioenergetic metabolism contributes to hematopoiesis control has not been reported. Based on the extensive findings supporting microRNA control by ApoE in mature myeloid cells, it was tested whether ApoE regulates hematopoiesis in hyperlipidemia through similar mechanisms by assessing whether the expression of ApoE in HSPC derived from hyperlipidemic mice modulates bioenergetic activities via the regulation of miR-146a and miR-142a. As shown in FIG.4A, the data show that bone marrow (BM) Lin- c-Kit⁺ (LK) cells derived from Apoe^h/h Ldlr^-/- mice express 60% more miR-146a while displaying a 40% reduction in levels of miR-142a in those derived from Apoe^-/- Ldlr^-/- mice. This pattern of microRNA expression paralleled a 50% decrease in the miR- 146a target, Slc2a1, the transcript for GLUT1. A similar level of control of the miR-142a target, Cpt1a, which was expressed at 40% greater levels in LK cells derived from Apoe^h/h Ldlr^-/- mice was observed (FIG.4B). Next, it was tested whether reduced levels of Slc2a1 in LK cells derived from Apoe^h/h Ldlr^-/- mice could reduce glucose uptake in HSPC compartments of these mice. Data in FIG.4C show that bone marrow and total splenic cells derived from Apoe^h/h Ldlr^-/- mice displayed reduced glucose uptake as measured by the absorption of 2-DG. Glucose uptake capacity was also assessed across subsets of HSPC by measuring 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4- yl)Amino)-2-Deoxyglucose (2-NBDG) uptake in these cells using flow cytometry. Data in FIGS.15A and 4D reveals lower levels of in 2-NBDG uptake in Lin⁺, Lin-, LK, Lin- c-Kit⁺ Sca- 1⁺ (LSK), CD34⁺ LSK, and CD34- LSK cells from Apoe^h/h Ldlr^-/- mice as compared to those of Apoe^-/- Ldlr^-/- mice. A reduction in glucose uptake across subsets of HSPC of Apoe^h/h Ldlr^-/- mice also corroborates with lower expression levels of GLUT1 on the surface of these cells with the exception for CD34- LSK cells (FIGS.15B and 4E). These findings are consistent with those from the study of mature myeloid cells as well as from a previous study reporting elevated levels of GLUT1-mediated glucose uptake in HSPC derived from Apoe^-/- mice (Sarrazy V, et al. Circ Res.2016;118(7):1062-77). Together, these findings provide substantial evidence for ApoE in regulating glucose uptake in HSPC via miR-146a controlled GLUT1 expression. Next, it was tested whether the effects of ApoE in regulating GLUT1-mediated glucose uptake and CPT1A expression in HSPC also lead to altered cellular metabolism to control hematopoiesis in hyperlipidemic mice. Because mitochondrial metabolism is important for hematopoiesis (Anso E, et al. Nat Cell Biol.2017;19(6):614-25), OCR was measured in BM Lin⁺ and LK cells of Apoe^h/h Ldlr^-/- and Apoe^-/- Ldlr^-/- mice. The data show that Apoe^h/h Ldlr^-/- Lin⁺ and LK cells displayed enhanced OxPHOS as seen by elevated basal and maximal respiration associated with a higher proton leak and ATP production compared with Apoe^-/- Ldlr^-/- Lin⁺ and LK cells (FIGS.4F-G). Then, the OCR associated with CPT1A-mediated mitochondrial FAO was measured by treating the LK cells of Apoe^h/h Ldlr^-/- and Apoe^-/- Ldlr^-/- mice with the CPT1A inhibitor etomoxir at a concentration of 4 µM as in prior assessments in primary myeloid cells (FIGS.2N-O and 3M-N). Data shown in FIGS.4H-I reveal a more pronounced drop in OCR upon etomoxir treatment of Lin⁺ and LK cells derived from Apoe^h/h Ldlr^-/- as compared to those from Apoe^-/- Ldlr^-/- cells, indicating that the elevated OxPHOS activity observed in the HSPC compartments of Apoe^h/h Ldlr^-/- mice is driven largely by CPT1A-dependent FAO. In contrast, Lin⁺ and LK cells derived from Apoe^h/h Ldlr^-/- mice displayed lower levels of basal and compensatory glycolysis, as well as a lower percentage of total PER produced from glycolytic activity (% PER from Glycolysis) as compared to those derived from Apoe^-/- Ldlr^-/- mice (FIGS. 4J-K). Bioenergetic control exerted by ApoE among HSPC contributes to suppressing hyperlipidemia-driven myelopoiesis in hyperlipidemic mice. Elevated GLUT1-mediated glucose uptake in HSPC deficient in ApoE expression has been reported to promote hyperlipidemia- driven myelopoiesis and hematopoiesis (Sarrazy V, et al. Circ Res.2016;118(7):1062-77). Therefore, it was assessed whether reduced glucose uptake caused by ApoE expression in the HSPC of Apoe^h/h Ldlr^-/- mice could serve to control excessive hematopoiesis and myelopoiesis caused by hyperlipidemia. At first, it was observed that Apoe^h/h Ldlr^-/- mice displayed smaller spleen sizes, reduced spleen weights, and lower splenic cell numbers as compared to those of Apoe^-/- Ldlr^-/- mice (FIGS.15C-E). Further, reduced cell numbers were detected across subsets of HSPC examined in Apoe^h/h Ldlr^-/- mouse spleens (FIGS.4L and 15F). This included reduced numbers of LSK cells, hematopoietic stem cells (HSC), multipotent progenitor cells (MPP), lymphomyeloid multipotent progenitor cells (LMPP), multipotent progenitor cells 1-4 (MPP1- 4), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP), and megakaryocyte-erythroid progenitors (MEP) (FIGS.4L and 15F). A similar phenotype was also detected among progenitor cells examined from the BM of Apoe^h/h Ldlr^-/- mice as compared to those of Apoe^-/- Ldlr^-/- mice (FIG.4M). This control of hyperlipidemia-driven hematopoiesis by ApoE mirrors an observed reduction in myelopoiesis in Apoe^h/h Ldlr^-/- mice as revealed by reduced numbers of circulating and splenic CD11b⁺ cells, Ly6C^hi monocytes, and neutrophils, as well as greater numbers of splenic Ly6C^lo monocytes (FIGS.4N-Q). Together, the data show that ApoE expression plays a role in regulating hyperlipidemia-driven hematopoiesis and myelopoiesis via the control of HSPC bioenergetic metabolism. Cell-intrinsic ApoE expression is required for effective control of microRNA-regulated metabolic signaling axes in myeloid cells of hyperlipidemic mice. Because the data in FIG.12B show a substantial accumulation of ApoE in the plasma of Apoe^h/h Ldlr^-/- mice, it was tested whether lipoprotein-associated ApoE could have contributed to modulate metabolic activities in myeloid cells collected from these mice. Thus, to address the importance for the source of ApoE in controlling microRNA-regulated metabolic signaling in myeloid cells, a series of syngeneic bone marrow transplantation (BMT) studies were performed. As shown in FIG.5A, myeloablated Wildtype BoyJ (CD45.1 Apoe^+/+) mice that had previously been injected with an AAV8-PCSK9 to drive hyperlipidemia (Bjorklund MM, et al. Circ Res.2014;114(11):1684-9; and Roche-Molina M, et al. Arterioscler Thromb Vasc Biol.2015;35(1):50-9), received bone marrow (BM) cells derived either from CD45.2 Apoe^-/- or Apoe^+/+ donors and were thereafter maintained on a Western high-fat diet (HFD). A reciprocal BMT in myeloablated HFD-fed Apoe^-/- CD45.2 mice that received BM cells from Apoe^-/- CD45.2 or Apoe^+/+ CD45.1 donors was performed (FIG.5A). In these experiments, the recipient mice achieved a 90% reconstitution of donor BM cells six weeks post-BMT (FIG.5B). Furthermore, these findings show that Apoe^+/+ ^ Apoe^+/+, Apoe^-/- ^ Apoe^+/+, and Apoe^-/- ^ Apoe^-/- mice did not show any notable differences in their lipoprotein profiles, total cholesterol, or total triglyceride levels (FIGS.5C-D) (Fazio S, et al. Proc Natl Acad Sci U S A.1997;94(9):4647-52). As expected, Apoe^-/- ^ Apoe^+/+ mice and Apoe^-/- ^ Apoe^-/- mice also showed drastically reduced levels of Apoe mRNA in circulating Ly6C^hi monocytes (FIG.5E). In contrast, Apoe^+/+ ^ Apoe^-/- mice did not display marked hyperlipidemia when fed a HFD (FIGS.5C-D) while also expressing similar levels of Apoe mRNA in their circulating monocytes as compared to Apoe^+/+ ^ Apoe^+/+ mice (Figure 5E). This is consistent with studies that documented a role of myeloid cell-derived ApoE in mediating lipoprotein clearance by the liver ⁹. Thus, to avoid the confounding effects caused by lower plasma lipoprotein and cholesterol levels on myeloid cell signaling, the Apoe^+/+ ^ Apoe^-/- subgroup of mice were not included into subsequent studies. Through studies of the three remaining groups of BMT mice, the effects of the source of ApoE expression in controlling the miR-146a and miR-142a signaling axes observed in myeloid cells derived from the Apoe^h/h Ldlr^-/- mouse model was tested. (FIGS.3A-P and 13A-M). The findings show that circulating Ly6C^hi monocytes collected from Apoe^-/- ^ Apoe^+/+ mice displayed a 60% reduction in miR-146a levels and a 30% upregulation in miR-142a levels as compared to cells derived from Apoe^+/+ ^ Apoe^+/+ mice (FIGS.5F-G). Furthermore, Apoe^-/- ^ Apoe^+/+ mice displayed a 30% increase in Slc2a1 mRNA (GLUT1) levels and a 30% decrease in Cpt1a mRNA levels in their circulating Ly6C^hi monocytes when compared to those collected from Apoe^+/+ ^ Apoe^+/+ mice (FIGS.5H-I). No significant differences was observed in the levels of these microRNAs and mRNAs in cells collected from Apoe^-/- ^ Apoe^+/+ and Apoe^-/- ^ Apoe^-/- mice (FIGS.5F-I). Thus, these findings support cell-intrinsic ApoE expression over lipoprotein-associated ApoE in controlling microRNA-regulated metabolism. Cell-intrinsic ApoE expression in myeloid cells controls chronic inflammation, hematopoiesis, and myelopoiesis caused by hyperlipidemia. To investigate the importance for the source of ApoE expression in controlling myeloid cell-driven chronic inflammation caused by hyperlipidemia, models of HFD-fed BMT mice detailed above (FIGS.5A-I) were used. Despite a similar hyperlipidemia, the mRNA expression levels of Il1b, Il6, Mcp1, and Tnf, were substantially upregulated in circulating Ly6C^hi monocytes derived from Apoe^-/- ^ Apoe^+/+ mice and Apoe^-/- ^ Apoe^-/- mice as compared to those derived from Apoe^+/+ ^ Apoe^+/+ mice (FIG.5J). In contrast, the anti-inflammatory cytokine Il10 showed an opposite expression pattern. Consistent with these findings, greater levels were observed of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-6, and IL-1β and lower levels of the anti-inflammatory cytokine IL-10 in the plasma of Apoe^-/- ^ Apoe^+/+ and Apoe^-/- ^ Apoe^-/- mice as compared to plasma derived from Apoe^+/+ ^ Apoe^+/+ mice (FIG.5K). Repeating the assessments of progenitor and mature hematopoietic cells in the first mouse model of hyperlipidemia (FIGS.3L-Q and 15C-F) among the three types of BMT mice confirmed the importance for cell-derived ApoE expression in regulating hematopoiesis in hyperlipidemic setting. The findings revealed greater numbers of LSK, HSC, MPP, LMPP, MPP1-4, CMP, GMP, and MEP cells in the BM and spleens of Apoe^-/- ^ Apoe^+/+ mice and Apoe^-/- ^ Apoe^-/- mice as compared to Apoe^+/+ ^ Apoe^+/+ mice (FIGS.5L-M). In line with this finding, both Apoe^-/- ^ Apoe^+/+ and Apoe^-/- ^ Apoe^-/- mice displayed greater numbers of circulating and splenic CD11b⁺ cells, Ly6C^hi monocytes, and neutrophils, as well as reduced numbers of splenic Ly6C^lo monocytes (FIGS.5N-O). Systemic delivery of miR-146a mimics or miR-142a inhibitors amplify the effects of ApoE expression in controlling glycolytic and mitochondrial metabolism in myeloid cells of hyperlipidemic mice. To further confirm the participation of miR-146a and miR-142a in regulating bioenergetic activities in macrophages, repeated systemic intravenous delivery was performed of 1 nmol of miR-146a mimics or miR-142a inhibitors to HFD-fed AAV8-PCSK9- injected Apoe^+/+ (Wildtype) mice twice a week for a total of four weeks (FIG.6A). While the RNA infusions did not change plasma cholesterol and lipoprotein profiles (FIGS.16A-C), delivery of miR-146a mimics elevated the miR-146a levels in splenic F4/80⁺ macrophages by 30% and had no impact on levels of miR-142a (FIG. S9D). This was accompanied with a 2-fold decrease in Slc2a1 mRNA (GLUT1) levels in these cells (FIG.16E). Moreover, similar treatments using miR-142a inhibitors reduced cellular miR-142a levels by 2-fold in splenic F4/80⁺ macrophages (FIG.16D), which upregulated the Cpt1a mRNA levels by 40% (FIG. 16E). The impact these findings had on altering bioenergetic activities in these cells was examined. FIGS.3R-S show that these microRNA treatments significantly increased OxPHOS in splenic F4/80⁺ macrophages derived from mice treated with either miR-146a mimics or miR- 142a inhibitors, resulting in elevated basal and maximal respiration associated with a higher proton leak and ATP production. Interestingly, miR-142a inhibitors caused a more profound elevation in OxPHOS as compared to miR-146a mimics (FIGS.6B-C). Furthermore. FIGS.3T- U reveal reduced glycolysis in splenic F4/80⁺ macrophages derived from mice treated with either miR-146a mimics or miR-142a inhibitors. In this case, the use of miR-146a mimics led to more profound reductions in glycolysis as compared to what was achieved with miR-142a inhibitor treatments (FIGS.6D-E). Together, the data in FIGS.6D-E and 16E support the observation in FIGS.3A-P, demonstrating a role for cellular ApoE expression and its miR-146a and miR-142a signaling axes in controlling immunometabolism by upregulating FAO and OxPHOS while dampening glycolytic activity in myeloid cells derived from hyperlipidemic mice. Systemic delivery of miR-146a mimics or miR-142a inhibitors reproduce the anti- inflammatory properties of ApoE expression in suppressing hyperlipidemia- and LPS-driven inflammation in myeloid cells. Next, it was assessed whether the systemic delivery of miR-146a mimics or miR-142a inhibitors could suppress inflammatory responses in hyperlipidemic mice. The findings presented in FIG.6F shows that a 4-week treatment with either form of the synthetic RNA led to a reduction in the pro-inflammatory cytokines IFN-γ, TNF-α, IL-6, and IL- 1β in plasma of HFD-fed Apoe^+/+ AAV8-PCSK9 mice. While treatments with miR-146a mimics caused a more profound reduction in levels of IFN-γ and IL-6, treatments with miR-142a inhibitors led to a more robust reduction in TNF-α (FIG.6F). These observations are in line with mRNA levels for Il1b, Il6, Mcp1, Tnf and Il10 among splenic F4/80⁺ macrophages derived from these mice (FIG.6G). Furthermore, while both forms of RNA treatments upregulated the mRNA expression of the M2 markers (Arg1, Retnla, and Chil3), antagonism of miR-142a led to a more robust effect (FIG.6G). Next, it was examined whether inhibiting miR-142a in vitro in Apoe^-/- BMDM could phenocopy the expression of ApoE to suppress inflammatory responses in these cells upon LPS- stimulation. Data in FIG.17A show a 50% reduction in the expression of Tnf, Il1b, Il6, and Mcp1 mRNA, in Apoe^-/- BMDM transfected with miR-142 inhibitor as compared to cells transfected with negative control oligonucleotides or non-transfected cells. Conversely, the inhibition of miR-146a in Apoe^+/+ BMDM elevated the gene expression levels of these pro- inflammatory cytokines upon LPS-stimulation by 1.5 to 2-fold (FIG.17B). It was also found that transfection of miR-142 inhibitor to human THP-1 macrophages protected against LPS- driven pro-inflammatory response by suppressing Tnf, Il6, and Mcp1 mRNA levels (FIG.17C). Furthermore, THP-1 macrophages transfected with miR-142 inhibitor showed elevated levels of M2 macrophage genes (Arg1, Retnla, and Chil3) upon exposure to IL-4 (FIG.17C). These data reveal that antagonism of miR-142a in human myeloid cells can favor a more robust M2 polarized anti-inflammatory phenotype. Together, the data provide substantial evidence supporting a role for cellular ApoE expression in modulating myeloid cell inflammatory responses via its regulation of microRNA homeostasis, including miR-146a and miR-142a. Systemic delivery of miR-146a mimics or miR-142a inhibitors suppressed hyperlipidemia-driven hematopoiesis and myelopoiesis by amplifying the effects of ApoE expression in bioenergetic control among HSPC. Next, the involvement of an ApoE-microRNA axis in the bioenergetic control of hematopoiesis was confirmed by using Lin⁺ and LK cells derived from HFD-fed AAV8-PCSK9 mice that had been treated with either miR-146a mimics or miR-142a inhibitors. The results show that infusions of miR-146a mimics to HFD-fed Apoe^+/+ mice increased miR-146a levels in their LK cells (FIG.7A), which led to a decrease in Slc2a1 (GLUT1) mRNA levels (FIG.7B). In contrast, infusions of miR-142a inhibitors led to a decrease in miR-142a levels in LK cells (FIG.7A), leading to an increase in Cpt1a mRNA levels (FIG.7B). In line with these findings, FIGS.7C-D show a significant increase in OxPHOS in LK cells derived from mice treated with miR-146a mimics or miR-142a inhibitors, resulting in elevated basal and maximal respiration associated with a higher proton leak and ATP production. Interestingly, miR-142a inhibitors treatments displayed an even more profound elevation in OxPHOS as compared to miR-146a mimics treatments (FIGS.7C-D). FIGS.7E-F also show reduced glycolysis in LK cells derived from mice treated with miR-146a mimics or miR-142a inhibitors with lower levels of PER produced from glycolytic activity. Furthermore, treatments with miR-146a mimics led to a more profound reduction in glycolysis as compared to treatments with miR-142a inhibitors (FIGS.7E-F). Together, the show ApoE expression regulates HSPC bioenergetic metabolism by sustaining FAO and OxPHOS while dampening glycolytic activity via the regulation of miR-146a and miR-142a and their mRNA target genes. Lastly, a role for microRNA control of hematopoiesis was confirmed. FIGS.7G-H show a reduction in the numbers of LSK, HSC, MPP, LMPP, MPP1-4, CMP, GMP, and MEP in the BM and spleens of HFD-fed AAV8-PCSK9 mice treated with miR-146a mimics or miR-142a inhibitors. Interestingly, a greater decrease in the number of hematopoietic progenitors among mice treated with miR-146a mimics (FIGS.7G-H) was found. Such downregulation in hematopoiesis mirrored a decrease in splenic CD11b⁺ cells, Ly6C^hi monocytes, and neutrophils as well as greater numbers of Ly6C^lo monocytes, with miR-146a mimics conferring a more profound control as compared to what could be achieved using miR-142a inhibitors (FIG.7I). It was also further observed that treatments with either miR-146a mimics or miR-142a inhibitors reduced the number of CD11b⁺ cells, Ly6C^hi monocytes, and neutrophils in the circulation of hyperlipidemic Apoe^+/+ AAV8-PCSK9 mice (FIG.7J). Together, the data identify cellular ApoE expression as an important regulator of hyperlipidemia-driven hematopoiesis and myelopoiesis via its regulation of miR-146a and miR-142a dependent bioenergetic metabolism. ApoE control of immunometabolism protects against vascular inflammation & atherosclerosis. Lastly, it was tested whether benefits that cell-intrinsic ApoE exerts in suppressing hyperlipidemia-driven inflammation could confer protective properties against vascular inflammation and atherosclerosis. To this end, flow cytometric analyses of immune cells released from aortas of hyperlipidemic mice was performed. In doing so, reduced levels of CD45⁺ leukocytes, CD11b⁺ cells, CD11b⁺ F4/80⁺ macrophages, Ly6C^hi monocytes, and neutrophils, as well as an expansion of Ly6C^lo monocytes in the aortas of Apoe^h/h Ldlr^-/- mice were observed as compared to Apoe^-/- Ldlr^-/- mice (FIGS.18A-B). It was next tested whether the reduced systemic and aortic inflammation conferred by cell-intrinsic ApoE expression protected these hyperlipidemic mice against atherosclerosis. To this end, an assessment of histological sections derived from the aortic root of Apoe^h/h Ldlr^-/- mice revealed substantially smaller atherosclerotic lesion areas than those of Apoe^-/- Ldlr^-/- mice (FIGS.18C-D). The extent of necrosis was further examined by measuring acellular areas in atheroma, recognized as a cardinal feature of advanced and vulnerable atherosclerotic lesions (Yurdagul A, et al. Front Cardiovasc Med.2017;4(86). The data shown in FIGS.18E-F demonstrate significantly reduced necrotic lesion areas in atheroma of Apoe^h/h Ldlr^-/- mice as compared to those of Apoe^-/- Ldlr^-/- mice. These findings further revealed profoundly smaller lipid-rich and macrophage-positive areas in the atheroma of Apoe^h/h Ldlr^-/- mice (FIGS.18G-H). Support for the potent atheroprotective properties of cell-intrinsic ApoE expression in hyperlipidemia come from the observations of reduced numbers of CD45⁺ cells in the aorta of Apoe^+/+ ^ Apoe^+/+ mice as compared to those of Apoe^-/- ^ Apoe^+/+ and Apoe^-/- ^ Apoe^-/- mice (FIG.19). Finally, the involvement of miR-146a and miR-142a in controlling vascular inflammation and atherosclerosis was supported by a reduction in aortic CD45⁺ cells observed in hyperlipidemic mice treated with miR-146a mimics and inhibitors of miR-142a (FIG.20). While significant differences in the numbers of CD11b⁺ cells or CD11b⁺ F4/80⁺ macrophages in the aorta of these mice were not observed (FIG.20), a significant reduction in aortic CD45⁺ cells in HFD-fed Apoe^+/+ AAV8-PCSK9 mice that received treatments with either miR-146a mimics or miR-142a inhibitors was found (FIG.20). Taken together, the data disclosed herein unveil ApoE-controlled microRNA-regulation of bioenergetic metabolism as an important element involved in controlling hematopoiesis and chronic inflammation in hyperlipidemia that likely serves an important role in suppressing the pathogenesis of atherosclerosis. ApoE is widely recognized for its pleiotropic properties that together control cardiovascular inflammation and atherosclerosis (Davignon J. Arterioscler Thromb Vasc Biol. 2005;25(2):267-9; and Alagarsamy J., et al. Int J Mol Sci.2022;23(17). Its role in controlling immunity and inflammation was recognized soon after its discovery as a ligand for plasma remnant lipoprotein clearance by the liver (Mahley RW. Science.1988;240(4852):622-30; Curtiss LK, and Boisvert WA. Curr Opin Lipidol.2000;11(3):243-51; and Hui DY, et al. J Biol Chem.1980;255(24):11775-81). However, mechanisms responsible for these effects have largely centered on its capacity to prevent an over accumulation of lipid in myeloid cells (Bonacina F, et al. Nat Commun.2018;9(1):3083; and Fazio S, et al. Proc Natl Acad Sci U S A. 1997;94(9):4647-52). Results of this study uncover immune regulatory properties of ApoE that center on its capacity to control cellular microRNA networks. In doing so, ApoE controls mitochondrial metabolism in myeloid cells and HSPC that together serve to limit chronic cardiovascular inflammation in mice with hyperlipidemia. The findings disclosed herein stem from an exhaustive assessment of energy utilization and mitochondrial function among macrophages and dendritic cells derived from Wildtype (Apoe^+/+), heterozygous (Apoe^+/-), and ApoE deficient (Apoe^-/-) mice. By using this strategy, it was determined that bone marrow derived macrophages and dendritic cells devoid of ApoE expression displayed increased glycolytic activity that was driven by a 50% greater uptake of glucose via NF-κB ^driven GLUT1-expression in response to LPS stimulation. Conversely, it was also found that when expressing one or two alleles of ApoE, these myeloid cells upregulate CPT1A that depletes stores of cellular neutral lipids and substantially improves OxPHOS and ATP production. Thus, these findings reveal the existence of an ApoE gene dose-dependency in the control of myeloid cell bioenergetic metabolism. To gain a mechanistic understanding for observations disclosed herein and the role of cellular ApoE expression in upregulating levels of miR-146a in monocytes and macrophages by fostering the expression of its host gene PU.1 (Spi1) (Li K, et al. Circ Res.2015;117(1):e1-e11). The assessment of this signaling axis highlighted its property for limiting inflammatory activity in myeloid cells caused by hyperlipidemia and LPS-stimulated NF-κB signaling (Li K, et al. Circ Res.2015;117(1):e1-e11). Results from this study reveal that this ApoE/microRNA axis also controls the expression of GLUT1 (Slc2a1) mRNA expression, a process recognized as a checkpoint for preventing myeloid cell hyperactivity in models of Type 1 inflammation (Obaid M, et al. Sci Rep.2021;11(1):232). The efficacy of this signaling circuit in suppressing excessive glycolytic metabolism was confirmed by the observations of reduced GLUT1 protein levels on the surface of wildtype mouse macrophages, which limited the bioavailability of glucose for rapid energy production by the cells in response to LPS exposure. Causal inference supporting this metabolic signaling axis derived from a restoration of ApoE expression and by the inhibition of NF-κB activity with the selective inhibitor BAY11-7085 in Apoe^-/- cells that similarly restricted cellular glucose uptake, its entry into glycolysis and the production of lactate when the cells were treated with LPS. The anti-glycolytic property of an ApoE/miR-146a axis in myeloid cells provided evidence that an ApoE-dependent microRNA circuit may be responsible for controlling OxPHOS. Evidence supporting this finding arose from the unbiased RNA sequencing of Apoe^+/+ and Apoe^-/- cells that revealed an altered microRNA repertoire in the absence of ApoE. While levels of miR-146a were confirmed to be downregulated in Apoe^-/- cells, other microRNAs were elevated. This finding alone illustrates the complexity associated with the ability for ApoE to control microRNA homeostasis. Among the 78 microRNAs identified as sensitive to ApoE expression included miR-142a. miR-142a was assessed for its actions in OxPHOS control as it had recently been reported to suppresses dendritic cell activation by targeting CPT1A, a functional component of the carnitine shuttle and FAO in the mitochondria (Sun Y, Oravecz- Wilson K, Bridges S, McEachin R, Wu J, Kim SH, Taylor A, Zajac C, Fujiwara H, Peltier DC, et al. miR-142 controls metabolic reprogramming that regulates dendritic cell activation. J Clin Invest.2019;129(5):2029-42). Remarkably, the findings probing miR-142a activity in macrophages and dendritic cells derived from Apoe^-/- mice revealed its capacity to suppress OxPHOS by downregulating CPT1A and fatty acid flux into mitochondria in these cells. Improved mitochondrial membrane potential and OxPHOS-derived ATP production in Apoe^-/- cells treated with miR-142a anti-sense oligonucleotides support an important role for this microRNA in driving mitochondrial metabolism. Furthermore, a direct role for cellular ApoE expression in driving this metabolic bias was shown by the ectopic expression of ApoE in Apoe^-/- cells that reduced miR-142a levels, hereby restoring CPT1A levels that improved mitochondrial membrane potential. In contrast, OxPHOS could be blunted in Apoe^+/+ BMDM by inhibiting CPT1A with etomoxir, providing further evidence that robust OxPHOS in Apoe^+/+ BMDM is driven primarily by CPT1A- dependent FAO, a process that was shown to be upregulated by ApoE via miR-142a downregulation. These findings were largely reproduced in cultured human THP-1 cells, providing translational significance for a miR-142a/CPT1A signaling axis that can serve to control immunometabolism and thereby inflammatory activity in human myeloid cells. An observed accumulation of numerous by-products of the TCA cycle as well as of amino acid metabolism, including dimethylglycine, glutamate, citrate, succinyl-CoA, malate, and even NAD⁺ in extracts of Apoe^+/+ versus Apoe^-/- macrophages mirrored that of IL-4- stimulated M2-like versus M0 macrophages. Such metabolic signatures further validate a role for ApoE in driving OxPHOS. Importantly, the buildup of these metabolites is likely to contribute additional layers of signaling properties to myeloid cells (Martinez-Reyes I, and Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun.2020;11(1):102). In particular, glycine metabolism regulates macrophage inflammatory response and atherosclerosis progression (Gan Z, et al. Front Immunol. 2021;12(762564); Liu Y, et al. Cell Rep.2021;36(4):109420; and Rodriguez AE, et al. Cell Metab.2019;29(4):1003-11 e4), while NAD⁺ improves the control of inflammation in macrophages and tissue repair activities (Minhas PS, et al. Nat Immunol.2019;20(1):50-63). Furthermore, the accumulation of these metabolites in Apoe^+/+ as compared to Apoe^-/- macrophages may also play a direct role in regulating microRNA homeostasis (Gan Z, et al. Front Immunol.2021;12(762564). In seeking to substantiate the in vitro observations linking ApoE to cellular bioenergetic control of metabolism, hypomorphic ApoE mice deficient in low density lipoprotein receptor expression (Apoe^h/h Ldlr^-/-) that display similar hyperlipidemia as Apoe^-/-Ldlr^-/- mice were studied. Despite their similar hyperlipidemia, the lipoprotein cholesterol profile of Apoe^h/h Ldlr^-/- mice is more akin to human hyperlipidemia as seen by an abundance in LDL and HDL cholesterol, in contrast to VLDL cholesterol that predominantly accumulates in plasma of Apoe^-/- Ldlr^-/- mice. Previous studies of these mice noted that sub-physiological levels of ApoE expression are sufficient to drive the miR-146a/NF-κB axis to control inflammation and atherosclerosis in these mice (Obaid M, et al. Sci Rep.2021;11(1):232). Results of this study further links the protective effect to the control of GLUT1 expression and glucose uptake in myeloid cells and HSPC. Remarkably, this study revealed that sub-physiological ApoE expression levels were also sufficient to suppress levels of miR-142a that led to increased CPT1A levels, reduced cellular neutral lipids, and a 30% increase in basal respiration in these cells. Collectively, ApoE-dependent microRNA control of metabolism had a profound impact on shaping myeloid cell compartments and their progenitor cells in these mice. This restricted an expansion of numerous myeloid cells populations in the circulation and the spleen that was apparent in Apoe^-/-Ldlr^-/- mice, including plasmacytoid DC that are increasingly associated with chronic inflammatory disorders including atherosclerosis (Macritchie N, et al. Arterioscler Thromb Vasc Biol.2012;32(11):2569-79; and Doring Y, et al. Circulation.2012;125(13):1673- 83). Increased OxPHOS activity in myeloid cells expressing even low levels of ApoE blunted the production of inflammatory cytokines when the cells were cultured ex-vivo with LPS. Together, the metabolic rheostat properties of ApoE expression resulted in a substantial reduction in aortic macrophage accumulation and atheroma lesion size and complexity in the aortic root of mice with an otherwise similar magnitude of hyperlipidemia. While studies of the Apoe^h/h Ldlr^-/- mouse model provided compelling in-vivo evidence supporting ApoE expression in driving microRNA-control of immunometabolism, they could not exclude the contribution of ApoE in plasma as a source of cellular signaling. Indeed, the cellular signaling and cholesterol efflux properties of lipoprotein-associated ApoE has previously been noted for its capacity to control HSPC hyperproliferation (Murphy AJ, et al. J Clin Invest.2011;121(10):4138-49; and Wang M, et al. Arterioscler Thromb Vasc Biol. 2014;34(5):976-84), as well as inflammatory cytokine expression and antigen presentation among mature myeloid cells (Bonacina F, et al. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation. Nat Commun.2018;9(1):3083). Conclusive in vivo evidence supporting ApoE expression as a dominant source of microRNA-controlled immunometabolism derived from the study of hyperlipidemic mice with hematopoietic systems sufficient or deficient in ApoE expression. Through a series of experiments performed with HSPC and mature myeloid cells derived from hyperlipidemic mice with a chimeric bone marrow revealed that even a normal complement of plasma ApoE could not rescue deficits of microRNA-regulated glycolysis and OxPHOS in the absence of cell-intrinsic ApoE expression, resulting in increased systemic and aortic inflammation. Furthermore, miR-146a and miR-142a were themselves validated for their contribution to ApoE-controlled immunometabolism through systemic delivery of RNA oligonucleotides in hyperlipidemic mice. While the control of glycolytic activity through agonism of miR-146a was highly effective in suppressing systemic and aortic inflammation (Li K, et al. Circ Res.2015;117(1):e1-e11), it may compromise Type I immunity owing to its potent control of NF-κB (Taganov KD, et al. Proc Natl Acad Sci U S A. 2006;103(33):12481-6; and Boldin MP, et al. J Exp Med.2011;208(6):1189-201). In contrast, potent upregulation of mitochondrial OxPHOS produced by antagonism of miR-142a was equally effective in suppressing hematopoiesis and cardiovascular inflammation. Importantly, unlike miR-146a agonisms, this strategy led to improved IL-10 production by myeloid cells, a cytokine recognized for resolving inflammation and atherosclerosis (Ip WKE, et al. Science. 2017;356(6337):513-9). Thus, targeting miR-142a as described herein raises plasma IL-10 levels in hyperlipidemic mice can be useful as a therapeutic approach to control cardiovascular inflammation and atherosclerosis without compromising Type I immunity. Together, the data described herein provides evidence that ApoE expression as a source of microRNA regulation in myeloid cells serves to control immunometabolism. The findings disclosed herein reveal a role for ApoE in controlling both innate and adaptive immunity that contributes to limit systemic and vascular inflammation in hyperlipidemia. Furthermore, the data offer new insight to reconcile findings from prior studies reporting protective properties of sub- physiological ApoE expression levels in suppressing cardiovascular inflammation and atherosclerosis (Ma Y, et al. PLoS One.2008;3(6):e2503; Gaudreault N, et al. Arterioscler Thromb Vasc Biol.2012;32(2):264-72; and Thorngate FE, et al. J Lipid Res.2003;44(12):2331- 8). They also open opportunities to gain a better understanding for ApoE isoform-specific modulation of inflammation that could derive from altered microRNA expression patterns. Animals. In vivo studies were conducted using Apoe^-/- Ldlr^-/- or hypomorphic Apoe^h/h Ldlr^-/- mouse strain by breeding Ldlr^-/- mice on a C57BL/6J background (Jackson Laboratories, ME) to Apoe^-/- or hypomorphic (Apoe^h/h) mice, respectively.12-week-old to 14-week-old male Apoe^-/- Ldlr^-/- or Apoe^h/h Ldlr^-/- mice were fed a rodent chow diet (PicoLab, USA) of equal nutritional value containing either 4.5% or 9% of fat (crude oil), respectively. Atherosclerosis analysis was performed in 30-week-old Apoe^-/- Ldlr^-/- or Apoe^h/h Ldlr^-/- mice that were fed the respective chow diets. In vivo infusions of microRNA inhibitors and mimics were conducted using C57BL/6J mice intravenously (i.v.) injected with 10¹¹ GC of AAV8-PCSK9. Six-week-old male AAV8- PCSK9-injected C57BL/6 wildtype mice were fed a Western diet (Research Diets, USA) for 2 weeks before being randomly assigned to be i.v. infused with miR-142a inhibitors, miR-146a mimics, negative control (scramble), or vehicle (PBS + Lipofectamine 3000 agents) for 4 weeks while remaining on the Western diet for the duration of the study. BMT studies were conducted (Peake K, et al. J Vis Exp.201598):e52553). Briefly, 6-week-old BoyJ mice (CD45.1 on C57BL/6J background) were injected with 10¹¹ GC of AAV8-PCSK9 and received a total of 100 mg/kg of Busulfan over the course of 5 days. These mice then received 2.4 x 10⁶ cells derived from the BM of Wildtype C57BL/6J or Apoe^-/- mice, and remained on a HFD for 6 weeks. Reciprocally, Apoe^-/- mice (CD45.2 on C57BL/6J background) also received 100 mg/kg of Busulfan over the course of five days, followed by 2.4 x 10⁶ BM cells from Apoe^-/- or BoyJ mice, and were subsequently maintained on a HFD for 6 weeks. Levels of bone marrow chimerism were measured at 2 and 4-week time point. Peripheral blood was collected by retro-orbital bleeding with heparinized micro- hematocrit capillary (Fisher Scientific, USA) in tubes containing 0.5M EDTA and spun at 1500 x g for 30 minutes in 4°C to collect the plasma. Cholesterol and triglycerides levels were measured from plasma using the Cholesterol E Assay Kit or L-Type Triglyceride M Assay Kit (Wako Diagnostics, Fujifilm, Japan). Data collection and analyses were conducted in a blinded- fashion. Mice were housed and bred in specific pathogen–free conditions. Primary cells and cell line. Bone marrow cells were flushed from the tibia and femurs of age-matched 6- to 12-week-old male Apoe^-/-, Apoe^+/-, or wildtype mice on C57BL/6J background. Cells were cultured in complete media containing DMEM (Corning, USA) supplemented with 10% fetal bovine serum (GIBCO, USA), 1% GlutaMax (GIBCO, USA), and 1% penicillin-streptomycin (GIBCO, USA) and differentiated with 25 ng/ml mouse M-CSF (Peprotech, USA) for 6 days in 37°C and 5% CO2. BMDM were then seeded into 12-well culture plates (Corning, USA) at a concentration of 3 x 10⁵ cells/well and stimulated with lipopolysaccharides (LPS) (Sigma Aldrich, USA) for 6 or 18 hours before collected for analysis. For bone marrow derived dendritic cells (BMDC), bone marrow cells were flushed from the tibia and femurs of age-matched 6- to 12-week-old male Apoe^-/-, Apoe^+/-, or wildtype mice on C57BL/6J background. Cells were cultured in complete media and differentiated with 25 ng/ml mouse GM-CSF (Peprotech, USA) for 6 days in 37°C and 5% CO2. Cells were collected in media suspension as immature BMDC. Cells were then seeded into 12-well culture plates (Corning, USA) at a concentration of 3 x 10⁵ cells/well and stimulated with lipopolysaccharides (LPS) (Sigma Aldrich, USA) for 6 or 18 hours before collected for analysis as mature BMDC. The human monocytic cell line (THP-1) was purchased from the UCSF Cell and Genome Engineering Core (CGEC) as an authenticated stock. Cells were cultured in RPMI 1640 medium (Corning, USA) supplemented with 10% fetal bovine serum (GIBCO, USA), 1% GlutaMAX (GIBCO, USA), and 1% penicillin-streptomycin (GIBCO, USA). THP-1 cells were grown and expanded in suspension in a T-75 flask (Fisher Scientific, USA) until a density of 1 x 10⁶ cells/mL. Cells were then seeded to a 12-well plate (Corning, USA) at a density of 4 x 10⁵ cells/well and differentiated into macrophages by culturing in 25 ng/mL phorbol 12-myristate 13-acetate (PMA) (Fisher Scientific, USA) for 48 hours. Cells were then cultured in PMA-free media for an additional 48 hours. Cells were then transfected with antisense oligonucleotide for 48 hours and subsequently treated with 100 ng/mL lipopolysaccharides (LPS) (Sigma Aldrich, USA) or 20 ng/mL human IL-4 (Peprotech, USA). Transfection of DNA plasmids and oligonucleotides in primary cells. For ectopic expression of apoE in Apoe^-/- BMDM and BMDC, the cells were cultured in OptiMEM (Life Technologies, USA) and transiently transfected with mouse Apoe cDNA clone or control expression plasmids (Origene, USA) using Lipofectamine 3000 (Life Technologies, USA) as per the manufacturer’s instructions. For microRNA inhibition experiments, antisense oligonucleotides targeting miR-146a/miR-142a or negative control (50 nM, Thermo Fisher, USA) were transfected into Apoe^+/+ (for miR-146a inhibition) or Apoe^-/- (for miR-142a inhibition) BMDM and BMDC using Lipofectamine RNAiMAX Reagent (Invitrogen, USA) according to the manufacturer’s protocol. Human THP-1 macrophages were also treated with miR-142a inhibitors (50 nM, Thermo Fisher, USA) according to manufacturer’s protocol. At 24 hrs or 48 hrs post transfection, cells were collected for downstream analysis. MH10398 (Thermo Fisher), mirVana^® miRNA inhibitor for hsa-miR-142-3p was used; and MC10722 (Thermo Fisher), mirVana^® miRNA mimic hsa-miR-146a-5p was used. Transfection and in vivo infusions of oligonucleotides. The oligonucleotides were prepared (Sun X, et al. Circ Res.2014;114(1):32-40). Briefly, 1 µl of 1 nmol/ µl antisense oligonucleotides targeting miR-142a (miR-142a inhibitors), miR-146a mimics, or negative control (Thermo Fisher, USA) was mixed with 100 µl PBS (Corning, USA). The transfection reagent was prepared by mixing 30 µl Lipofectamine RNAiMAX (Thermo Fisher, USA) with 70 µl PBS (Corning, USA). The 100 µl of oligonucleotides + PBS mixture was subsequently mixed with the 100 µl transfection reagent to create a 200 µl final mixture by pipetting 100x. This mixture was infused i.v. to HFD-fed AAV8-PCSK9-injected mice via retro-orbital injection twice a week (1 nmol/mouse/injection). Protein extraction and immunoblotting. Cells were lysed in RIPA Buffer (Cell Signaling, USA) containing cOmplete, Mini, EDTA-free Protease Inhibitor Cocktail (Roche, Switzerland) and 1 mM PMSF (Cell Signaling, USA). Protein concentrations were measured using Pierce BCA Protein Assay Kit (Thermo Fisher Scientific, USA). A total of 15 µg of proteins was diluted with PBS to 37.5 µL, then mixed with 12.5 µL 4x Laemmli buffer (Bio-Rad, USA). Samples were subsequently heated at 95°C for 5 minutes. Samples were then loaded on a 10% SDS-PAGE gel and transferred onto PVDF membrane (Bio-Rad, USA). The membranes were blocked with 5% non-fat milk dissolved in PBS for one hour and then incubated with primary antibodies overnight at 4°C. Primary antibodies include anti-CPT1A (1:200, Santa Cruz, USA) and anti-GAPDH (1:1000, Cell Signaling, USA). After 4 washes in PBS containing 0.1% Tween (PBST), membranes were incubated with corresponding HRP-conjugated secondary antibodies: anti-Mouse IgG-HRP (1:1000, Santa Cruz, USA) or anti-Rabbit IgG-HRP (1:1000, Thermo Fisher Scientific, USA) for 1 hour and washed in PBST. Signals were visualized after incubation with Amersham ECL Prime substrate and imaged using an ImageQuant LAS 4000. Quantification was analyzed using ImageJ. RNA extraction and gene expression analysis using qRT-PCR. Total RNA isolated from cells was extracted using Qiazol Lysis Buffer (QIAGEN, Germany) and purified using the RNeasy Mini Kit (QIAGEN, Germany) according to the manufacturer’s protocol. RNA was quantified using Nanodrop (Thermo Fisher Scientific, USA) and reverse transcribed using the iScript Reverse Transcription Supermix (Bio-Rad, USA) for mRNA or the miRCURY LNA RT Kit (QIAGEN, Germany) for microRNA analysis. qPCR reactions were performed using the Fast SYBR Green Master Mix (Applied Biosystems, USA) for mRNA or the miRCURY LNA SYBR Green PCR Kit (QIAGEN, Germany) for microRNA and processed using a QuantStudio 7 Flex Real-Time PCR System. Ct values were normalized to the housekeeping genes Gapdh and B2m. For microRNA expression, UniSp6 was used as a spike-in control while U6 snRNA, miR-16-5p, and miR-21-5p (QIAGEN, Germany) were used as reference genes. Reactions were done in triplicates. Small RNA library preparation, sequencing, and analysis. Total RNA isolated from cells was extracted using Qiazol Lysis Buffer (QIAGEN, Germany) and purified using the RNeasy Mini Kit (QIAGEN, Germany) according to the manufacturer’s protocol. Small RNA libraries were generated using Illumina TruSeq Small RNA Sample kit (Illumina, USA) according to the manufacturer’s instructions. The libraries were then sequenced on the HiSeq 2500 (Illumina, USA) to generate single end 50 bp reads. The raw sequence image files from the Illumina HiSeq in the form of bcl files were converted to the fastq format using bcltofastq v.2.19.1.403 and checked for quality to ensure the quality scores did not deteriorate at the read ends. Reads shorter than 15 nts were discarded and after adaptor trimming, the 30 bases below a quality score of 30 were also trimmed. The reads are first mapped to a library of UniVec contaminants, a collection of common vector, adaptor, linker and PCR primer sequences collated by the NCBI. They are then mapped to mouse rRNA sequences obtained from NCBI. Finally, small RNA mapping and annotation was done using sRNABench (v.3-3.2) where reads are mapped to the mouse genome (GRCm38) and transcriptome using a transcriptome which contains all ensembl genes plus annotations for microRNAs, as obtained for miRBase (v.22). Alignment files are then processed by sRNABench into miRNA counts matrices for further analysis. Glucose uptake assay in macrophages and HSPC. BMDM or peritoneal macrophages were seeded at a density of 150,000 cells/well in a 24-well culture plate with or without LPS for 18 hours. The next day, BMDM were preincubated with KRPH buffer containing 2% bovine serum albumin, 20 mM HEPES, 5 mM KH2PO4, 1 mM MgSO4, 1 mM CaCl2, 136 mM NaCl, and 4.7 mM KCl, pH 7.4 (each from Sigma Aldrich, USA) for 40 minutes. Subsequently, 10 µL/well of 10 mM 2-deoxyglucose (2-DG) was added and incubated for 20 minutes. Next, cells were washed 3x with PBS to remove exogenous 2-DG. BMDM were then lysed and 2-DG uptake was processed using a Glucose Uptake Assay Kit (Abcam, USA) according to the manufacturer’s protocol. Absorbance reading was measured at OD 412 nm on a microplate reader (Molecular Devices, USA). For 2-NBDG uptake, pre-stained HSPC or BMDM were incubated with 2-NBDG (Invitrogen, USA) for 30 min in 37C with 5% CO₂. The cells were then washed with PBS and analyzed for 2-NBDG uptake using a CytoFLEX S cytometer (Beckman, USA). Assessments of neutral lipids accumulation and mitochondrial membrane potential in macrophages. For analysis of neutral lipids accumulation, BMDM or peritoneal macrophages were stained with LipidTOX (Invitrogen, USA) (1:250) for 30 minutes at room temperature and analyzed using a CytoFLEX S cytometer (Beckman, USA). For analysis of mitochondrial activity, cells were stained with tetramethylrhodamine at final concentrations of 0.1 μM. The cells were then incubated in 37C for 30 minutes. Cells were then analyzed using a CytoFLEX S cytometer (Beckman, USA). Multiplex immunoassay analysis of cytokines production. Total splenic cells, bone marrow cells, and BMDM were plated at 900,000 cells/well in a 6-well plate and stimulated with LPS for 6 hours. The conditioned media was then collected and spun at 400 x g for 10 minutes to remove the cells. Mouse plasma was collected as indicated above. TNF-α, IL-6, IL- 1β, IL-10, and IFN-γ cytokine levels in these conditioned media and plasma were measured using the V-Plex Mouse Custom Cytokine Kit (Meso Scale Discovery, USA) according to the manufacturer’s protocol. Measurements of lactate production by cells. BMDM were plated at 900,000 cells/well in a 6-well plate. Cells were either unstimulated or stimulated with LPS for 18 hours. The conditioned media was then collected and spun at 400 x g for 10 minutes to remove the cells. Levels of lactate in these conditioned media were measured using the L-Lactate Colorimetric Assay Kit (Abcam, USA) according to the manufacturer’s protocol. Absorbance was measured at OD 450 nm using a microplate reader (Molecular Devices, USA). Metabolomic screening in BMDM. BMDMs were seeded in a 6-well cell culture plate at a density of 50,000/well, and incubated in complete media at 37°C & 5% CO2 overnight. Cells were gently washed 4x with DPBS before freezing at -80C. For metabolite extraction, cells were extracted with 1 mL HPLC-grade methanol/water 80:20. Cell lysates were centrifuged at 18,000 x g for 10 min. Supernatants were collected for downstream metabolomic analysis. The samples were evaporated using a stream of nitrogen. Subsequently metabolites were reconstituted in 50% acetonitrile in HPLC-grade water, vortexed and centrifuged to remove any debris. Samples were analyzed by Ultra-High-Performance Liquid Chromatography and High-Resolution Mass Spectrometry and Tandem Mass Spectrometry (UHPLC-MS/MS). Specifically, the system consisted of a Thermo Q-Exactive in line with an electrospray source and an Ultimate3000 (Thermo Fisher, USA) series HPLC consisting of a binary pump, degasser, and auto-sampler outfitted with an Xbridge Amide column (Waters; dimensions of 4.6mm × 100mm and a 3.5μm particle size). Mobile phase A contained 95% (vol/vol) water, 5% (vol/vol) acetonitrile, 10mM ammonium hydroxide, 10mM ammonium acetate, pH = 9.0; and mobile phase B was 100% Acetonitrile. The gradient was as follows: 0 min, 15% A; 2.5 min, 30% A; 7 min, 43% A; 16 min, 62% A; 16.1-18 min, 75% A; 18-25 min, 15% A with a flow rate of 400μL/min. The capillary of the ESI source was set to 275°C, with sheath gas at 45 arbitrary units, auxiliary gas at 5 arbitrary units, and the spray voltage at 4.0kV. In positive/negative polarity switching mode, an m/z scan range from 70 to 850 was chosen and MS1 data was collected at a resolution of 70,000. The automatic gain control (AGC) target was set at 1x10⁶ and the maximum injection time was 200 ms. The top 5 precursor ions were subsequently fragmented, in a data-dependent manner, using the higher energy collisional dissociation (HCD) cell set to 30% normalized collision energy in MS2 at a resolution power of 17,500. Data acquisition and analysis were carried out by Xcalibur 4.1 software and Tracefinder 4.1 software, respectively (both from Thermo Fisher Scientific, USA). Subsequent analysis was performed by normalizing the peak area of each metabolite to the total ion count of the sample, which represented the cumulative value of the recorded peaks. Normalization to Total Ion Counts was carried out in Microsoft Excel. T-tests with multiple comparisons adjustments, fold change analysis, and hierarchical clustering analysis on Wildtype and Apoe^-/- BMDMs was carried out using the Metaboanalyst 5.0 program using R (Pang Z, et al. Nucleic Acids Res.2021;49(W1):W388- W96). Assessments of leukocyte numbers and cellular markers using flow cytometry. Mice were anesthetized with isoflurane (Forane, Baxter, USA) and peripheral blood was collected by retro- orbital bleeding with heparinized micro-hematocrit capillary (Fisher Scientific, USA) in tubes containing 0.5M EDTA. Red blood cells were lysed in RBC lysis buffer (BioLegend, USA). Nonspecific binding was blocked with TruStain FcX Ab (BioLegend, USA) for 10 min at 4°C in FACS buffer (Ca²⁺/Mg²⁺-free PBS with 2% FBS and 0.5 mM EDTA) before staining with appropriate Abs: CD11b (clone M1/70), Ly-6C (clone HK1.4), CD115 (clone AFS98), and CD45 (clone 30-F11) (BioLegend, USA) for 30 min at 4C. The antibody dilutions ranged from 1:200 to 1:100. Splenocytes were isolated using mechanical dissociation. Briefly, spleens were mashed using the bottom of a 3 mL syringe (BD Biosciences). The cells were then passed through a 70 um cell strainer and incubated in RBC lysis buffer (BioLegend, USA). Nonspecific binding was blocked with TruStain FcX Ab (BioLegend, USA) for 10 min at 4°C in FACS buffer before staining with appropriate Abs: CD11b (clone M1/70), Ly-6C (clone HK1.4), Ly-6G (clone 1A8), and CD11c (clone N418). Splenic dendritic cells were analyzed using the following Abs panel: CD11b (clone M1/70), Ly-6C (clone HK1.4), CD11c (clone N418), I-A/I-E (clone M5/114.15.2), B220 (clone RA3-6B2), CD86 (clone GL-1), CD80 (clone 16-10A1). The antibody dilutions ranged from 1:200 to 1:100. For detection of GLUT1 on cellular surface, BMDM, peritoneal macrophages, and pre- stained bone marrow cells were incubated with anti-GLUT1 (species) at 1:50 concentration in FACS buffer for 30 min in 4C. Cells were then washed once with PBS and incubated with anti- species (1:200 concentration) in FACS buffer for 30 min in 4°C. For analysis of nuclear NF-κB activity, the nuclei of BMDM, peritoneal macrophages, and pre-stained myeloid cells were permeabilized using the Foxp3/Transcription Factor Staining Buffer Set (eBioscience, USA) and stained with anti-phospho-p65 subunit (species) at 1:100 concentration for 60 min in room temperature according to the manufacturer’s protocol. For aorta digestion, single cell suspension from an aorta segment including the aortic arch and thoracic aorta was prepared by incubation with an enzyme mixture containing 400 U/mL Collagenase I, 120 U/mL Collagenase XI, 60 U/mL Hyaluronidase, and 60 U/mL DNase I (all from Sigma Aldrich, USA) in Hank’s balanced salt solution for 50 minutes in 37°C. Cells were then passed through a 70-µm cell strainer and spun down at 300 x g for 5 minutes in 4°C. Resulting cell pellet was blocked with TruStain FcX Ab (BioLegend, USA) for 10 min at 4°C in FACS buffer before staining with appropriate Abs: CD11b (clone M1/70), Ly-6C (clone HK1.4), Ly-6G (clone 1A8), CD45 (clone 30-F11), and F4/80 (clone BM8). The antibody dilutions ranged from 1:200 to 1:100. Cell types were then analyzed using a CytoFLEX S cytometer (Beckman, USA). Collection of circulating Ly6C^hi monocytes was performed using a FACSAria Fusion Cell Sorter (BD Biosciences, USA). Isolation and analysis of mature immune cells and HSPC subsets. Peritoneal cells from Apoe^h/h Ldlr^-/- or Apoe^-/- Ldlr^-/- mice were collected by lavage with 10 mL DPBS (Corning, USA) using a 16-G needle. Cells were then incubated with red cell lysis buffer (BioLegend, USA) for 5 min and cultured in 6-well cell culture plates (Corning, USA) in complete media. After two hours, cells were washed once with DPBS (Corning, USA) and replenished with fresh complete media. Adherent cells were then collected for downstream analysis as peritoneal macrophages after one hour. CD11c⁺ cells from Apoe^h/h Ldlr^-/- or Apoe^-/- Ldlr^-/- mice were collected from the spleens of these mice. Briefly, splenic cells were collected with centrifuged at 300 x g, 5 min at 4°C, resuspended in red cell lysis buffer (BioLegend, USA) for 5 min and run through a 40 µm strainer.1 x 10⁷ splenic cells were incubated with CD11c MicroBeads UltraPure (Miltenyi, Germany) and passed through a LS column that is placed on a quadroMACS separator (Miltenyi, Germany). Positively selected cells were collected as CD11c⁺ cells for downstream analysis. F4/80⁺ cells from miR-142a inhibitors or miR-146a mimics-infused mice were collected from the spleens. Briefly, splenic cells were collected with centrifuged at 300 x g, 5 min at 4°C, resuspended in red cell lysis buffer (BioLegend, USA) for 5 min and run through a 40 µm strainer.1 x 10⁷ splenic cells were incubated with F4/80 MicroBeads UltraPure (Miltenyi, Germany) and passed through a LS column that is placed on a quadroMACS separator (Miltenyi, Germany). Positively selected cells were collected as F4/80⁺ cells for downstream analysis. For isolation and analysis of HSPC, cells were collected from the bone marrows or spleens of 10- to 14-week-old male Apoe^h/h Ldlr^-/- or Apoe^-/- Ldlr^-/- mice and centrifuged at 300 x g, 5 min at 4C, resuspended in red cell lysis buffer (BioLegend, USA) for 5 min and run through a 40 µm strainer. The cells were stained with a lineage-marker cocktail of biotinylated anti-CD4 (RM4-5), -CD8 (53-6.7), -B220/CD45RA (RA3-6B2), -TER-119 (TER-119), -Gr-1 (RB6-8C5), and -CD127 (IL-7Ra/A7R34) antibodies (each from BioLegend, USA). These cells were then stained with anti-CD34 (RAM34, eBioscience, USA), anti-CD150 (TC15-12F12.2, BioLegend, USA), anti-CD48 (Invitrogen, USA), anti-Sca-1 (D7, Invitrogen, USA) anti-CD135 (A2F10, Invitrogen, USA) anti-c-Kit (2B8, Life Technologies, USA), anti-CD16/32 (93, BioLegend, USA), anti-CD41 (MWReg30, BioLegend, USA) and streptavidin-BV786 (BD Biosciences, USA) to detect biotinylated antibodies. Cells were then analyzed using a CytoFLEX S cytometer (Beckman, USA). For isolation of HSPC, Lin- c-Kit⁺ cells were isolated from the bone marrows of 10- to 14-week-old male Apoe^h/h Ldlr^-/- or Apoe^-/- Ldlr^-/- mice using the mouse Lineage Cell Depletion Kit, and mouse CD117 MicroBeads (both from Miltenyi, Germany) according to the manufacturer’s protocol. Briefly, 1 x 10⁷ bone marrow cells were incubated with a Biotin- Antibody Cocktail of biotin-conjugated monoclonal antibodies CD5, CD45R (B220), CD11b, Anti-Gr-1 (Ly-6G/C), 7-4 and Ter-119 (Miltenyi, Germany). Cells were then incubated with Anti-Biotin MicroBeads (Miltenyi, Germany) and passed through a LS column that is placed on a quadroMACS separator (Miltenyi, Germany). Negatively selected cells were collected as Lin- cells. Next, Lin- cells were incubated with CD117 MicroBeads (Miltenyi, Germany) and passed through a LS column placed on a quadroMACS separator (Miltenyi, Germany). Positively selected cells were collected as Lin- c-Kit⁺ cells. These cells were subsequently used for Seahorse extracellular flux analysis or collected in Qiazol lysis buffer (Qiagen, Germany) for RNA extraction. Histological assessments of atherosclerosis. Aortic root sections were stained and quantified (Bouchareychas L, et al. Cardiovasc Res.2015;108(1):111-23; and Bouchareychas L, et al. Cell Rep.2020;32(2):107881). Beginning at the base of the aortic root, 120 sections per mice were cut at 10 µm, and arranged in 4 sections per slide. Atherosclerotic lesions in the aortic root were quantified by staining with oil red O (ORO) (Sigma-Aldrich, USA) to reveal neutral lipids in 20 cross-sections, 50 µm apart starting at the coronary ostium and extending through the base of the aortic valve. The slides were counterstained with modified Mayer’s hematoxylin (Thermo Fisher Scientific, USA). Lesion area was defined as ORO-positive area and quantified by averaging six sections that were spaced 50 µm apart, starting from the base of the aortic root. For macrophage staining, sections were labeled with a primary rat anti-mouse MOMA-2 antibody (Cedarlane Labs, USA) and detected with an Alexa Fluor 488 anti-rat IgG (H+L) antibody (Life Technologies, USA). Plaque necrosis was quantified by measuring the area of Hoechst-negative and MOMA2-negative areas in the intima. Images were captured with a Zeiss Observer microscope and analyzed using ZEN (Zeiss, Germany). Seahorse extracellular flux analysis. For BMDM, cells were plated at 60,000 cells/well into XFe24 cell culture microplates (Agilent, USA) and incubated overnight at 37°C and 5% CO2 with or without LPS stimulation. The following day, the cells were washed with Seahorse XF DMEM assay buffer (Agilent, USA) supplemented with 10 mM glucose (Agilent, USA), 1 mM pyruvate (Agilent, USA), and 2 mM glutamine (Agilent, USA) and incubated for 1 hour at 37°C without CO₂. For measurements of oxidative phosphorylation, OCR and ECAR were measured using the mitochondrial stress test kit (Agilent, USA) in response to 1 µM Oligomycin, 2 µM Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and 0.5 µM Rotenone/Antimycin A (R/AA). For measurements of fatty acid oxidation, OCR and ECAR were measured in cells treated with 4 µM Etomoxir (Sigma Aldrich, USA) followed by 1 µM Oligomycin (Agilent, USA). For measurements of glycolytic activity, PER was measured using the glycolytic rate assay (Agilent, USA) in response to 0.5 µM R/AA and 50 mM 2-deoxy-D- glucose (2-DG). The measurements were performed with the Seahorse XFe-24 Bioanalyzer (Agilent, USA). After OCR measurements, cells were incubated in Hoechst (1:1000) diluted in Live Cell Imaging Solution (Invitrogen, USA) and imaged under a Zeiss Observer microscope. Total cell counts were measured using ImageJ. For peritoneal macrophages and F4/80⁺ splenic macrophages, cells were plated at 60,000 cells / well into XFe24 cell culture microplates (Agilent, USA) and incubated at 37°C and 5% CO2 for two hours. The cells were then washed with Seahorse XF DMEM assay buffer (Agilent, USA) supplemented with 10 mM glucose (Agilent, USA), 1 mM pyruvate (Agilent, USA), and 2 mM glutamine (Agilent, USA) and incubated for 1 hour at 37°C without CO2. For measurements of oxidative phosphorylation, OCR and ECAR were measured using the mitochondrial stress test kit (Agilent, USA) in response to 1 µM Oligomycin, 2 µM Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and 0.5 µM Rotenone/Antimycin A (R/AA). For measurements of fatty acid oxidation, OCR and ECAR were measured in cells treated with 4 µM Etomoxir (Sigma Aldrich, USA) followed by 1 µM Oligomycin (Agilent, USA). For measurements of glycolytic activity, PER was measured using the glycolytic rate assay (Agilent, USA) in response to 0.5 µM R/AA and 50 mM 2-deoxy-D-glucose (2-DG). The measurements were performed with the Seahorse XFe-24 Bioanalyzer (Agilent, USA). After OCR measurements, cells were incubated in Hoechst (1:1000) diluted in Live Cell Imaging Solution (Invitrogen, USA) and imaged under a Zeiss Observer microscope. Total cell counts were measured using ImageJ. For HSPC, Lin- c-Kit⁺ cells were plated at 150,000 cells/well into XFe24 cell culture microplates (Agilent, USA) coated with Cell-Tak (Corning, USA). The cells were then washed with Seahorse XF DMEM assay buffer (Agilent, USA) supplemented with 10 mM glucose (Agilent, USA), 1 mM pyruvate (Agilent, USA), and 2 mM glutamine (Agilent, USA) and incubated for 1 hour at 37°C without CO2. For measurements of oxidative phosphorylation, OCR and ECAR were measured using the mitochondrial stress test kit (Agilent, USA) in response to 1 µM Oligomycin, 2 µM Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and 0.5 µM Rotenone/Antimycin A (R/AA). For measurements of fatty acid oxidation, OCR and ECAR were measured in cells treated with 4 µM Etomoxir (Sigma Aldrich, USA) followed by 1 µM Oligomycin (Agilent, USA). For measurements of glycolytic activity, PER was measured using the glycolytic rate assay (Agilent, USA) in response to 0.5 µM R/AA and 50 mM 2-deoxy-D-glucose (2-DG). The measurements were performed with the Seahorse XFe- 24 Bioanalyzer (Agilent, USA). After OCR measurements, cells were incubated in Hoechst (1:1000) diluted in Live Cell Imaging Solution (Invitrogen, USA) and imaged under a Zeiss Observer microscope. Total cell counts were measured using ImageJ. The OCR measurements from cells were normalized to cell number and used to calculate all parameters of mitochondrial activity and glycolytic functions. Data were analyzed using XFe Wave software. For measurements of glycolytic activity using the Seahorse Glycolytic Rate Assay, glycoPER is calculated by taking the difference between total PER and mitochondrial PER. Basal Glycolysis is calculated as the glycoPER (difference between total PER and mitochondrial PER) before R/AA injection. % PER from Glycolysis is calculated the % of total PER that is attributed by Basal Glycolysis (glycoPER) before R/AA injection. Compensatory Glycolysis is calculated as the total PER after R/AA injection and before 2-DG injection. For measurement of fatty acid oxidation, the Acute Response is calculated as the difference in OCR prior to and after Etomoxir treatment. Statistical analysis was performed with GraphPad Prism v8, using the unpaired, two- tailed, Student’s t test (two groups) and one-way or two-way analysis of variance (ANOVA) with post-tests, Holm-Sidak, as indicated in figure legends for multiple groups. *p < 0.05, **p < 0.01, ***p < 0.001 ****p < 0.0001. Normality test was performed using the Shapiro-Wilk test on GraphPad Prism v8, with p > 0.05 indicating normal distribution. The error bars represent the mean ± the standard error of the mean (SEM unless stated). The experiments were repeated at least twice or performed with independent samples. Example 2: Apolipoprotein E expression in macrophages communicates immunometabolic signaling that controls hyperlipidemia-driven hematopoiesis and inflammation via exosomes While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles including exosomes is not known. Through the study of exosomes produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-exo) and ApoE deficient (EKO-BMDM-exo) mice, the results show an important role for apoE expression in regulating their cell signaling properties. WT-BMDM-exo communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p that reduced NF-κB signaling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyltransferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-exo exerted opposite effects by reducing cellular levels of apoE and miR-146a- 5p, which increased NF-κB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-exo increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4+ T lymphocytes, EKO-BMDM-exo drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM- exo into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-exo increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE- dependent immunometabolic signaling by macrophage exosomes was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics and miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, these findings demonstrate a property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted exosomes. Characterization and in vitro assessment of cell signaling properties of exosomes produced by Apoe-/- and Wildtype macrophages. Fully differentiated Apoe-/- and Wildtype BMDM were cultured in exosome-depleted medium for 24 hours. Exosomes secreted by these BMDM were purified using cushioned-density gradient ultracentrifugation (C-DGUC), a method that allows for a gentle concentration and purification of exosomes from conditioned culture medium and biofluids (Duong P, et al. PLoS One.2019;14(4):e0215324). Nanoparticle tracking analysis revealed similar particle concentration of 5.2 x 10¹⁰ and 5.5 x 10¹⁰ particles/mL and average mode size of 98 and 95 nm for exosomes derived from EKO-BMDM-exo and WT- BMDM-exo, respectively (FIGS.22A-C). The data show that both Apoe-/- and Wildtype BMDM secreted the same quantity of exosomes in a 24 hr period, averaging 6.5 x 10⁹ nano- particles per million cells for both conditions (FIG.31A). Morphological assessment of EKO- BMDM-exo and WT-BMDM-exo using transmission electron microscopy revealed an expected cup-shaped morphology and size averaging 100 nm (FIG.22D). Such isolates also showed similar average protein concentrations of 59 and 63 μg/mL for EKO-BMDM-exo and WT- BMDM-exo, respectively (FIG.31B). Western blot analysis showed the presence of exosomal proteins, including CD9, CD63, and CD81, and the absence of cell-associated proteins Calnexin and GM130 in 1.5 x 10⁹ particles of EKO-BMDM-exo or WT-BMDM-exo (FIG.22E). Despite sharing similar biophysical characteristics, WT-BMDM-exo displayed apoE immunoreactivity (FIG.22E), a finding consistent with prior studies of EVs and exosomes derived from macrophages (Zheng P, et al. Cell Death Dis.2018;9(4):434) and neutrophils (He Y, et al. J Clin Invest.2021;131(3)). Importantly, using size-exclusion chromatography, the results demonstrate that apoE-containing WT-BMDM-exo isolated by the C-DGUC approach are free of apoE-HDL (FIG.22F) that are likely also produced by the cultured BMDM and could otherwise serve as a confounding mediator of cellular signaling. Next, it was assessed whether EKO-BMDM-exo and WT-BMDM-exo displayed altered cell-signaling properties. These experiments were carried out by first testing their rate of cellular uptake by treating naïve BMDM with 2 x 10⁹ particles/mL of PKH26-labeled EKO-BMDM- exo, WT-BMDM-exo, or PBS as control and measured the fluorescent intensity in recipient cells after a 2-hour incubation period using fluorescent microscopy. Data in FIGS.31C-D shows similar cellular internalization efficiencies for both forms of exosomes. Next, naïve BMDM and BM-derived dendritic cells (BMDC) were incubated with EKO- BMDM-exo or WT-BMDM-exo at a concentration of 2 x 10⁹ particles/mL for 18 hours and subsequently stimulated the cells with 100 ng/mL lipopolysaccharides (LPS) for 6 hours. Data in FIGS.22F-G show that BMDM/BMDC treated with EKO-BMDM-exo displayed increased expression of pro-inflammatory cytokines and M1 macrophage marker genes (Tnf, Il6, Il1b, and Mcp1), as well as antigen-presenting and co-stimulatory molecules (H2-Ab1, Cd86, and Cd80) following LPS stimulation. In contrast, WT-BMDM-exo treatments attenuated the expression of these genes in LPS-stimulated BMDM and BMDC, even when compared to PBS treatments (FIGS.22G-H). Taken together, these results demonstrate a previously unsuspected role for apoE expression by macrophages in modulating protective cell-signaling properties of their secreted exosomes. Macrophage exosomes modulate cellular apoE levels and phagocytosis in recipient macrophages. Next, it was tested whether Apoe expression by macrophages could influence the ability for their exosomes to modulate apoE levels in recipient macrophages, a process important to macrophage polarization and inflammatory activity (Baitsch D, et al. Arterioscler Thromb Vasc Biol.2011;31(5):1160-8). The assessment was carried out by incubating naïve wildtype BMDM with exosomes produced by both cell types at a concentration of 2 x 10⁹ particles/mL for 18 hours. While a change in Apoe mRNA levels in recipient cells was not observed (FIG. 31E), it was noted that exposure to WT-BMDM-exo increased apoE protein levels by 2-fold as compared to PBS exposure (FIGS.23A-B). In contrast, exposure to EKO-BMDM-exo reduced apoE protein levels by 1.5-fold as compared to PBS exposure (FIGS.23A-B). Then, it was tested whether the modulation of cellular apoE levels by macrophage exosomes extended beyond modulating inflammatory gene expression levels in response to LPS. For this, it was assessed whether an enrichment or depletion of cellular apoE levels produced by an exposure to the two forms of BMDM exosomes, respectively, could differentially impact the phagocytic properties of recipient macrophages, a process reported to be sensitive to cellular apoE levels (Grainger DJ, et al. J Immunol.2004;173(10):6366-75). Remarkably, while the exposure to WT-BMDM-exo enhanced the phagocytic uptake of apoptotic cells by naïve BMDM (FIGS.23C-D), the exposure to EKO-BMDM-exo exerted an opposite effect. Specifically, EKO-BMDM-exo reduced the phagocytic properties of naïve wildtype BMDM to levels observed in naïve Apoe-/- BMDM (FIGS.23C-D). Mechanistically, data shown in FIGS. 23E-F demonstrate that the exposure to WT-BMDM-exo caused an enrichment of MerTK on the macrophage cell surface, a receptor central to the clearance of apoptotic cells (Thorp E, et al. Arterioscler Thromb Vasc Biol.2008;28(8):1421-8). In contrast, an exposure to EKO-BMDM- exo reduced MerTK cell-surface density on recipient macrophages that paralleled their reduced phagocytic capacity of apoptotic cells. Together, these findings show that ApoE expression by macrophages increases the capacity for their exosomes to control inflammatory signaling and effector functions in recipient macrophages by increasing cellular apoE levels. ApoE expression dictates the capacity for macrophage exosomes to suppress glucose uptake and glycolysis in recipient myeloid cells via a miR-146a/NF-κB axis. It was tested whether macrophage exosomes to modulate bioenergetic metabolism in recipient naïve BMDM were sensitive to cellular apoE expression in the parental cell. The capacity for EKO-BMDM- exo to communicate metabolic signaling to recipient myeloid cells was assessed. First, the ability of EKO-BMDM-exo to modulate both basal and LPS-stimulated aerobic glycolysis in recipient BMDM using a Seahorse Glycolytic Rate Assay to measure the glycolytic proton efflux rate (glycoPER) was assessed. As shown in FIGS.34A and B, naïve macrophages treated with EKO-BMDM-exo displayed increased levels of basal and compensatory glycolysis, as well as an increase in proton efflux rate produced from glycolytic activity as compared to macrophages treated WT-BMDM-exo and PBS both under basal condition and following LPS- stimulation. In seeking to uncover mechanisms to explain these observations, it was next tested whether treatments of EKO-BMDM-exo altered miR-146a-5p levels in recipient myeloid cells, a microRNA that is downregulated in apoE-deficient monocytes and macrophages (Li K, et al. Circ Res.2015;117(1):e1-e11). Interestingly, it was noted that a quantity of 2 x 10⁹ particles/mL of EKO-BMDM-exo suppressed miR-146a-5p levels by 50% in cultured naïve BMDM and BMDC as compared to a similar number of PBS-treated cells (FIGS.24C and 32A), a finding that paralleled the observed reduction in cellular apoE levels (Figures 2A-B). Next, it was examined whether the downregulation of miR-146a-5p exerted by EKO-BMDM-exo could alter cellular inflammatory signaling via mRNA target genes. Findings shown in FIGS.24D and 32B confirm an expected upregulation of canonical miR-146a-5p targets Traf6 and Irak1, two central mediators of NF-κB signaling (Li K, et al. Circ Res.2015;117(1):e1-e11; Taganov KD, et al. Proc Natl Acad Sci U S A.2006;103(33):12481-6; and Boldin MP, et al. J Exp Med. 2011;208(6):1189-201), in naïve BMDM and BMDC treated with EKO-BMDM-exo and subsequently stimulated with LPS for 6 hours. It was also observed an enhanced nuclear accumulation of phosphorylated NF-κB p65 subunit in LPS-stimulated BMDM pre-treated with EKO-BMDM-exo as compared to BMDM treated with WT-BMDM-exo or PBS (FIG.24E). As expected, an upregulation of apoE protein levels in naïve BMDM and BMDC exposed to WT- BMDM-exo was observed (FIGS.23A-B) exerted protective properties by increasing miR-146a- 5p levels (FIGS.24C and S32A) resulting in suppressed NF-κB signaling (FIGS.24D-E and 32B). As the NF-κB signaling pathway has been recognized as a major driver of GLUT1- mediated glucose uptake and glycolysis (Obaid M, et al. Sci Rep.2021;11(1):232), it was next tested whether the miR-146a/NF-κB axis controlled by EKO-BMDM-exo contributed to control cellular glucose uptake and glycolytic activity. The findings show that both BMDM and BMDC treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo upregulated levels of GLUT1 mRNA (Slc2a1) (FIGS.24F and 32C) and surface protein density (FIG.24G) upon stimulation with LPS. Increased cell-surface GLUT1 in BMDM treated with EKO-BMDM-exo led to enhanced glucose uptake in these cells as measured by the cellular uptake of 2-deoxyglucose (2-DG) (FIG. 24H). Increased levels of lactate, the end-product of aerobic glycolysis caused by LPS- stimulation (Kelly B, and O'Neill LA. Cell Res.2015;25(7):771-84) was also recorded, in the conditioned media of LPS-stimulated BMDM pre-treated with EKO-BMDM-exo (Figure 3I). In contrast, it was observed that WT-BMDM-exo treatments suppressed levels of GLUT1 mRNA (Slc2a1) and cell-surface levels in naïve BMDM and BMDC (FIGS.24F-G and 32C) that resulted in reduced 2-DG uptake and lactate production upon LPS-stimulation (FIGS.24H-I). Building on the findings linking EKO-BMDM-exo to miR-146a-5p control of NF-κB- driven glycolytic activity, it was tested whether treatments of EKO-BMDM-exo could modulate the transcriptomic profile in recipient macrophages. Assessments were carried out via unbiased sequencing of RNA isolated from cultured naïve BMDM treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. FIGS.324J and 32D revealed 150 genes that were differentially expressed between these three sets of BMDM. Among these included two genes involved in the glycolytic pathway (Aldh2 and Pkm) and six genes recognized to drive glycolytic activity (Cd9, Fth1, Dio2, and Pgd) (31-35) that were found to be highly enriched in naïve BMDM treated with EKO-BMDM-exo as compared to cells treated with WT-BMDM-exo or PBS. This pattern of gene expression was further confirmed by qRT- PCR in naïve BMDM and BMDC treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT- BMDM-exo, or PBS (FIGS.24K and 32E). Taken together, the data show that pro-glycolytic signaling effects communicated by EKO-BMDM-exo are exerted due to a lack of apoE expression in the parental cells. ApoE expression dictates the capacity for macrophage exosomes to communicate FAO and OxPHOS to recipient myeloid cells via a miR-142a/CPT1A axis. In view of these findings documenting the capacity for EKO-BMDM-exo to drive glycolytic activity in recipient cells, it was next examined whether they had the ability to modulate OxPHOS. Consistent with this idea, the RNA-seq data shown in FIGS.324J and 32D identified the gene coding for carnitine palmitoyltransferase 1A (Cpt1a), an important driver of FAO and OxPHOS, to be suppressed in naïve BMDM treated with EKO-BMDM-exo. In contrast, this gene was enriched in BMDM treated with WT-BMDM-exo as compared to those treated with PBS treatment. qRT-PCR confirmed this pattern of gene expression by showing a 30% increase in Cpt1a mRNA levels in naïve BMDM/BMDC treated with WT-BMDM-exo and a 40% decrease in Cpt1a mRNA levels in naïve BMDM/BMDC treated with EKO-BMDM-exo as compared to cells treated with PBS (FIGS.25A and 33A). It was also observed a 20% increase and 45% decrease in CPT1A protein levels in naïve BMDM treated with WT-BMDM-exo and EKO-BMDM-exo, respectively, as compared to cells treated with PBS (FIGS.25B-C). It was next sought to identify the mechanism responsible for the bidirectional control of CPT1A by EKO-BMDM-exo and WT-BMDM-exo treatments. The expression of miR-142a-3p in naïve BMDM/BMDC treated with the two forms of exosomes or PBS as control. The results show that miR-142a-3p levels were enriched by 90% in BMDM/BMDC treated with EKO-BMDM-exo (FIGS.25D and 33B), while they were reduced by 40% in cells treated with WT-BMDM-exo (FIGS.25D and 33B). Next, it was assessed whether a bidirectional control of the miR-142a/CPT1A axis by EKO-BMDM-exo or WT-BMDM-exo treatments could serve to differentially modulate FAO and OxPHOS in recipient cells. The oxygen consumption rate (OCR) was measured in BMDM treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS under basal and LPS-stimulated conditions for 18 hours using the Seahorse Mito Stress Assay. The data show that unstimulated naïve BMDM treated with WT-BMDM-exo displayed enhanced OxPHOS as seen by elevated basal and maximal respiration associated with a higher proton leak and ATP production compared to PBS-treated cells (FIGS.25E and F). In contrast, naïve BMDM treated with EKO-BMDM-exo displayed similar levels of OxPHOS as compared to PBS-treated cells in basal conditions (FIGS.25E and F). A substantial reduction of OxPHOS in BMDM was also observed across the three treatments upon LPS-stimulation, with cells treated with WT-BMDM-exo retaining more robust basal respiration and ATP production (FIGS.25E and F). Stemming from the data shown in FIGS.25A-C that support a role for EKO-BMDM-exo in suppressing CPT1A expression, it was tested whether levels of OCR were associated with CPT1A-mediated mitochondrial FAO by treating BMDM with the CPT1A inhibitor etomoxir following their exposure to EKO-BMDM-exo, WT-BMDM-exo, or PBS, respectively. For these experiments, etomoxir was used at a working concentration of 4 µM, which allows to target CPT1a activity without causing cellular oxidative stress known to occur at concentrations greater than 5 µM (O'Connor RS, et al. Sci Rep.2018;8(1):6289). Data shown in FIGS.25G-H reveal that, despite higher OCR at basal state, unstimulated BMDM treated with WT-BMDM- exo display a more substantial drop in OCR upon etomoxir treatment as compared to cells treated with EKO-BMDM-exo or PBS, indicating that the elevated OxPHOS in BMDM treated with WT-BMDM-exo is driven primarily by CPT1A-dependent FAO. Interestingly, EKO- BMDM-exo treatments further lowered CPT1A-dependent FAO as compared to PBS treatments as seen by a smaller drop in OCR upon etomoxir treatment (FIGS.25G-H). Furthermore, it was observed that LPS-stimulated BMDM displayed minor drops in OCR upon etomoxir treatment as compared to unstimulated cells. In contrast, naïve BMDM treated with WT-BMDM-exo displayed a more pronounced drop in OCR as compared to BMDM treated with EKO-BMDM- exo or PBS (FIGS.25G-H). Taken together, the data demonstrate a role for apoE expression in macrophages that is responsible for producing exosomes capable of communicating OxPHOS and FAO to recipient myeloid cells. ApoE expression dictates the capacity for macrophage exosomes to drive lipid mobilization, oxidative stress responses, and mitochondrial metabolism in recipient myeloid cells. A gene ontology (GO) enrichment assessment was performed in naïve BMDM treated with WT-BMDM-exo vs. cells treated with EKO-BMDM-exo by subjecting the RNA-seq data in FIGS.24J and 32D to the Database for Annotation, Visualization and Integrated Discovery (DAVID) tool (Huang DW, et al. Genome Biol.2007;8(9):R183). This approach provided an enrichment in sets of genes involved in oxidative stress responses, glutathione metabolism, and ABC transporters in naïve BMDM treated with WT-BMDM-exo (FIG.25I), processes known to control mitochondrial oxidative stress (Kerksick C, and Willoughby D. J Int Soc Sports Nutr. 2005;2(38-44) and cellular lipid efflux (Tall AR, et al. Cell Metab.2008;7(5):365-75), respectively. Indeed, WT-BMDM-exo treatments enhanced the expression of the selenoproteins and glutathione peroxidase genes (Selenow, Selenom, Selenop, Selenon, Gpx1, and Gpx3) (FIGS.24J, 25J, 32D and 33C). Interestingly, an enrichment was also observed in genes involved in the phagosome pathway (FIG.25I) in naïve BMDM treated with WT-BMDM-exo, which parallels the data in FIGS.23C-D, supporting their increased capacity for the phagocytic uptake of apoptotic Jurkat cells. In sharp contrast, an assessment of the RNA-seq data in FIGS. 24J and 32D, confirmed by qRT-PCR data in BMDM & BMDC (FIGS.25J and 33C), revealed a substantial reduction in the expression of genes involved in these biological processes in naïve BMDM treated with EKO-BMDM-exo. This includes the lipid transporter Abca1, the selenoproteins Selenow, Selenom, Selenop, and Selenon, as well as the glutathione peroxidases Gpx1 and Gpx3. Together, these findings support the finding that apoE expression is important for macrophages to communicate OxPHOS and mitochondrial metabolism to recipient cells via exosomes. Next, it was assessed whether changes in the transcriptomic profiles recorded in BMDM treated with the two forms of exosomes could lead to functional changes in cellular metabolism. The accumulation of neutral lipids in naïve BMDM with LipidTOX staining followed by detection using flow cytometry upon treatment with exosomes using a dose of 2 x 10⁹ particles/mL was measured first. Data shown in FIG.25K revealed a 54% increase in LipidTOX mean fluorescent intensity (MFI) in naïve BMDM treated with EKO-BMDM-exo as compared to those treated with PBS. In contrast, WT-BMDM-exo treatments reduced LipidTOX MFI by 71% in naïve BMDM as compared to PBS-treatments and 81% as compared to EKO-BMDM- exo-treatments and Apoe-/- BMDM alone (FIG.25K). The accumulation of reactive oxygen species was measured next in naïve BMDM treated with both forms of exosomes at a concentration of 2 x 10⁹ particles/mL using CellROX staining detected by flow cytometry. Data in FIG.25L reveal a 39% increase in CellROX MFI in naïve BMDM treated with EKO-BMDM-exo as compared to PBS-treated cells. In contrast, WT- BMDM-exo treatments reduced the CellROX MFI by 72% as compared to PBS-treated cells and 81% as compared to naïve BMDM treated with EKO-BMDM-exo or Apoe-/- BMDM alone (FIG.25L). Consistent with the data shown in FIG.25L, a 48% and 110% increase in mitochondrial superoxide (MitoSOX) accumulation was observed in naïve BMDM treated with EKO-BMDM-exo as compared to naïve BMDM treated with PBS or WT-BMDM-exo, respectively (FIG.25M). Such increase in cellular and mitochondrial oxidative stress conferred by EKO-BMDM-exo treatments contributed to the prolonged opening of the mitochondrial transition pores as shown by FIG.25N, which resulted in a 41% and 58% reduction in mitochondrial Calcein AM retention as compared to naïve BMDM treated with PBS or WT- BMDM-exo, respectively (FIG.25N). Such adverse effects caused by EKO-BMDM-exo treatments on reducing mitochondrial health contributed to a lower mitochondrial membrane potential (ΔΨm) as detected by Tetramethylrhodamine (TMRM) staining. FIG.25O revealed a 29% and 40% drop in the TMRM MFI in naïve BMDM treated with EKO-BMDM-exo as compared to naïve BMDM treated with PBS or WT-BMDM-exo, respectively. Finally, the levels of glutathione (GSH) and glutathione disulfide (GSSG) were measured in cells treated with 2 x 10⁹ particles/mL of both forms of BMDM exosomes. Results in FIG.25P show that naïve BMDM treated with WT-BMDM-exo displayed greater levels of GSH as well as the GSH:GSSG ratio, indicative of more robust protection against oxidative stress and improved cellular health (Owen JB, and Butterfield DA. Methods Mol Biol. 2010;648(269-77). In contrast, BMDM treated with EKO-BMDM-exo showed reduced levels of GSH and a GSH:GSSG ratio (FIG.25P), highlighting detrimental effects caused by these exosomes in predisposing recipient cells to oxidative stress. Remarkably, treatments with EKO- BMDM-exo communicated a similar magnitude of detrimental effects to naïve BMDM as was detected when examining Apoe-/- BMDM alone across the different measurements in FIGS. 25K-P. Together, these data further support an important role for apoE expression in macrophages that results in the production of exosome capable of communicating mitochondrial metabolism and oxidative stress control in recipient myeloid cells. Loss of apoE expression in macrophages results in exosomes that promote CD4+ T lymphocyte activation and proliferation. Next, it was assessed whether macrophage exosomes can control adaptive immune responses, and whether a loss of apoE expression can be detrimental. αCD3/αCD28-stimulated CD4+ T lymphocytes were treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. Then unbiased RNA sequencing was performed to assess changes in the transcriptomic profiles of these cells upon exosome treatments and identified 37 differentially expressed genes (FIG.26A). Among these, d three genes were identified that are important members of the T-cell receptor complex (Cd3e, Cd247, and Cd4) and Il2rg, an important component of cytokine receptors on CD4+ T lymphocytes (FIG.26A). GO enrichment analysis using the DAVID tool (Huang DW, et al. Genome Biol.2007;8(9):R183) of the RNA-seq data from CD4+ T lymphocytes treated with EKO-BMDM-exo or WT-BMDM-exo (FIG.26A), identified an enrichment of genes involved in the positive regulation of T cell activation, T cell receptor signaling pathway, and cell surface receptor pathway (FIG.26B). In view of these findings, a T lymphocyte proliferation assay was performed using carboxyfluorescein succinimidyl ester (CFSE)-labeled CD4+ T lymphocytes stimulated with αCD3/αCD28 beads and treated every two days with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for a period of four days. It was found that the mitotic index of CD4+ T lymphocytes treated with EKO-BMDM-exo was 36% higher than in cells treated with WT-BMDM-exo or PBS (FIG.26C). This finding was consistent with data shown in FIG.26D, demonstrating reduced levels of Annexin V, a marker of apoptosis, in αCD3/αCD28-stimulated CD4+ T lymphocytes treated with 2 x 10⁹ particles/mL of EKO- BMDM-exo, indicating that the lower number of apoptotic cells in this treatment group is associated with increased cellular proliferation. Next, the cellular activation of naïve CD4+ T lymphocytes exposed to EKO-BMDM-exo or WT-BMDM-exo upon stimulation with αCD3/αCD28 beads was examined. The data in FIG.26E show that an exposure to EKO- BMDM-exo increased the cell surface density of the activation markers CD69 and CD25 in the recipient cells. Furthermore, this also led the cells to produce higher levels of the Th1 inflammatory cytokine IFN-γ (FIG.26F). Together, the data provide evidence an important new property for macrophage apoE expression in controlling T lymphocyte activation via communication by exosomes. ApoE expression dictates the capacity for macrophage exosomes to suppress systemic inflammation and activation of myeloid cells in hyperlipidemic mice. In view of the in vitro findings supporting the capacity for EKO-BMDM-exo to shift macrophage cellular metabolism toward a glycolytic phenotype, it was assessed whether these exosomes could exert such properties in vivo to drive inflammatory responses sensitive to elevated glycolysis (Koelwyn GJ, et al. Nat Immunol.2018;19(6):526-37; and Tabas I, and Bornfeldt KE. Circ Res. 2020;126(9):1209-27) by repeatedly infusing EKO-BMDM-exo, WT-BMDM-exo, or PBS intraperitoneally (i.p.) to hyperlipidemic mice. Prior to exosome infusions, recipient six-week- old C57BL/6J mice were first treated intravenously with a recombinant adeno-associated virus vector serotype 8 encoding a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and fed a high-fat Western Diet (WD) (Maxwell KN, and Breslow JL. Proc Natl Acad Sci U S A.2004;101(18):7100-5; Bjorklund MM, et al. Circ Res. 2014;114(11):1684-9; Roche-Molina M, et al. Arterioscler Thromb Vasc Biol.2015;35(1):50-9; and Lu H, et al. Arterioscler Thromb Vasc Biol.2016;36(9):1753-7). These mice displayed similar levels of hyperlipidemia, with cholesterol and triglycerides levels of 660 and 215 mg/dL, respectively, after six weeks of high-fat WD feeding (FIG.34A-B). Furthermore, an assessment of the plasma lipoprotein profile in these mice showed an accumulation of remnant lipoproteins that is similar to the profile displayed by the Ldlr-/- mouse model fed a high-fat diet (FIG.34C) (Maxwell KN, and Breslow JL. Proc Natl Acad Sci U S A.2004;101(18):7100-5; Bjorklund MM, et al. Circ Res.2014;114(11):1684-9; Roche-Molina M, et al. Arterioscler Thromb Vasc Biol.2015;35(1):50-9; and Lu H, et al. Arterioscler Thromb Vasc Biol.2016;36(9):1753-7). Next, the biodistribution of EKO-BMDM-exo and WT-BMDM-exo was assessed by infusing i.p.1 x 10¹⁰ particles of 1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindotricarbocyanine Iodide (DiR)-labeled exosomes or PBS as control into WD-fed AAV8-PCSK9 mice. Following 6 hours post infusion, the presence of DiR-positive exosomes was detected in the circulation (FIGS.27A and 35), as well as the epididymal white adipose tissues, lungs, livers, brains, kidneys, aortas, spleens, bones, and intestines (FIGS.627B and 35). Our findings did not show any noticeable difference in the biodistribution of DiR-labeled EKO-BMDM-exo and WT- BMDM-exo in hyperlipidemic mice. Next, the mice were treated with either 1 x 10¹⁰ particles of EKO-BMDM-exo or WT- BMDM-exo, a dose that represents approximately 2 to 5% of total exosomes in mouse plasma (Bouchareychas L, et al. iScience.2021;24(8):102847), or PBS, three times/week (every two days) for four weeks while maintaining the mice on WD. The impact of such treatments on the accumulation of plasma cytokines were measured using a multiplex immunoassay. The data show that EKO-BMDM-exo infusions raised levels of the inflammatory cytokines IFN-γ, TNF- α, IL-6, and IL-1β in the circulation (FIG.27C). Interestingly, WT-BMDM-exo infusions reduced levels of TNF-α and IL-6 in the plasma of these mice (FIG.27C). Next, the accumulation of these cytokines in the conditioned media of LPS-stimulated bone marrow and splenic cells derived from these mice was measured. Data in FIG.27D indicates a substantial accumulation of TNF-α, IL-6, and IL-1β in the conditioned media of these cells when derived from mice infused with EKO-BMDM-exo. Consistent with the plasma cytokine data in FIG. 27C, a reduction in the production of TNF-α and IL-6 cytokines from these cells was also observed when derived from mice infused with WT-BMDM-exo. Further, elevated gene expression in these cytokines and M1 macrophage markers (Tnf, Il6, Il1b, and Mcp1) and reduced gene expression in M2 macrophage markers (Arg1, Retnla, and Chil3) was observed in peritoneal macrophages derived from mice that received EKO-BMDM-exo infusions as compared to those that received infusions of WT-BMDM-exo or PBS (FIG.27E). Moreover, WT-BMDM-exo infusions reduced the mRNA levels of the pro-inflammatory cytokines Tnf and Il6 while increasing the M2 markers (Arg1, Retnla, and Chil3) in the peritoneal macrophages (FIG.27E). An assessment of dendritic cells (Ly6C- MHCII+ CD11c+) derived from the spleens of these mice also revealed an increase in the antigen-presenting major histocompatibility complex class II (MHC-II), as well as the co-stimulatory molecules CD86 and CD80, on the surface of these cells when derived from mice infused with EKO-BMDM-exo (FIG.27F). Interestingly, WT-BMDM-exo infusions led to reduced expression of CD86 and CD80 on the surface of splenic dendritic cells even when compared to those derived from PBS-treated mice (FIG.27F). ApoE expression dictates the capacity for macrophage exosomes to improve mitochondrial health & function while suppressing glucose uptake and oxidative stress in myeloid cells of hyperlipidemic mice. Next, the capacity of the two forms of BMDM exosomes to modulate the metabolic properties of primary myeloid cells derived from hyperlipidemic mice was assessed. Using flow cytometry, it was found that circulating Ly6Chi monocytes derived from WD-fed AAV8-PCSK9 mice infused with EKO-BMDM-exo displayed increased glucose uptake as seen by the absorption of (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2- Deoxyglucose) (2-NBDG) (FIG.27G) and neutral lipid accumulations as seen by LipidTOX staining (FIG.27H). The results also increased levels of cellular reactive oxygen species (FIG. 27I) and mitochondrial superoxides (FIG.27J) in circulating Ly6Chi monocytes examined from these mice. Such increased cellular levels of oxidative stress led to lower mitochondrial ΔΨm as revealed by TMRM staining (FIG.27K). In contrast, circulating Ly6Chi monocytes of WD-fed AAV8-PCSK9 mice infused with WT-BMDM-exo displayed decreased cellular glucose uptake, neutral lipid and reactive oxygen species accumulation, along with mitochondrial superoxides (FIGS.27G-J). Furthermore, they displayed improved ΔΨm (FIG.27K). Building on the in vivo data indicating a capacity of macrophage apoE to communicate immunometabolic signaling via exosomes, it was assessed whether infusions of EKO-BMDM- exo into WD-fed AAV8-PCSK9 mice could modulate the expressions of target genes and microRNA revealed through our in vitro experiments with cultured primary BMDM and BMDC. The findings show that peritoneal macrophages collected from mice infused with EKO- BMDM-exo also displayed reduced levels of miR-146a-5p while displaying increased levels of miR-142-3p (FIGS.27L-M), consistent with the findings in cultured naïve BMDM treated with these exosomes in FIGS.3C and 4D. Furthermore, peritoneal macrophages derived from WD- fed AAV8-PCSK9 mice infused with EKO-BMDM-exo displayed increased expression of genes involved in the propagation of NF-κB signaling, and those involved in glycolytic activity (Traf6, Irak1, Aldh2, Pkm, Cd9, Fth1, Dio2, and Pgd) (FIG.27E). In contrast, these cells exhibited reduced expression of genes involved in FAO, cholesterol efflux, and oxidative stress protection (Cpt1a, Abca1, Selenow, Selenom, Selenop, Selenon, Gpx1, and Gpx3) (FIG.27E). Taken together, these data provide evidence that macrophage apoE expression in regulating the immune and metabolic modulatory effects of their secreted exosomes when tested in a hyperlipidemic in vivo environment. Loss of apoE expression in macrophages results in exosomes that enhance hyperlipidemia-driven hematopoiesis and myelopoiesis. As apoE deficiency in hematopoietic stem and progenitor cells (HSPC) has been reported to drive hematopoiesis and myelopoiesis in hyperlipidemic mice (Murphy AJ, et al. J Clin Invest.2011;121(10):4138-49), it was next investigated whether infusions of EKO-BMDM-exo could communicate similar effects to drive excessive hyperlipidemia-driven HSPC proliferation. Unlike the prior findings documenting a reduction of hematopoiesis by WT-BMDM-exo, it was found that hyperlipidemic WD-fed AAV8-PCSK9 mice infused with EKO-BMDM-exo displayed increased cell numbers across the subsets of bone marrow HSPC (FIGS.28A-B). This included elevated numbers of Lin- Sca-1+ c-Kit+ (LSK) cells, hematopoietic stem cells (HSC), multipotent progenitor cells (MPP), lymphomyeloid multipotent progenitor cells (LMPP), multipotent progenitor cells 1-4 (MPP1- 4), common myeloid progenitors (CMP), granulocyte-macrophage progenitors (GMP), and megakaryocyte-erythroid progenitors (MEP) (FIGS.28A-B). A similar phenotype was further detected among progenitor cells examined from the spleens of mice infused with EKO-BMDM- exo as compared to those infused with WT-BMDM-exo or PBS (FIGS.36A & 28C). Such acceleration of hyperlipidemia-driven hematopoiesis in WD-fed AAV8-PCSK9 mice infused with EKO-BMDM-exo augmented myelopoiesis as revealed by increased numbers of circulating and splenic CD11b+ cells, Ly6Chi monocytes, and neutrophils (FIGS.36B & 28D- F). Together, the data provide evidence for macrophage apoE expression for the production of exosomes capable of controlling hyperlipidemia-driven hematopoiesis and myelopoiesis. These findings thereby demonstrate a feedback property of myeloid cell apoE expression in modulating chronic leukocytosis and inflammation in hyperlipidemia. Systemic infusions of miR-146a mimics or miR-142a inhibitors substitute for apoE in suppressing hyperlipidemia-driven hematopoiesis and myelopoiesis in hyperlipidemic mice. Next, it was tested whether the control of hyperlipidemia-driven hematopoiesis and myelopoiesis by macrophage-derived exosomes was in part dependent on the modulation of miR-146a-5p and miR-142a-3p in recipient cells by performing repeated intravenous (i.v.) infusions of 1 nmol of miR-146a mimics or miR-142a inhibitors to WD-fed Apoe-/- mice twice a week for a total of four weeks (FIG.29A). While infusions of RNA mimics or antagonists did not alter the levels of plasma cholesterol in these mice (FIG.37A), delivery of miR-146a mimics elevated the miR-146a levels in splenic monocytes by 50% and had no impact on levels of miR- 142a-3p (FIGS.37B-C). Moreover, similar treatments using miR-142a inhibitors reduced cellular miR-142a-3p levels by 95% in splenic monocytes (FIG.37C). Infusions of miR-146a mimics or miR-142a inhibitors suppressed the numbers of LSK, HSC, MPP, LMPP, MPP1-4, CMP, GMP, and MEP in the bone marrows of WD-fed Apoe-/- mice (FIGS.29B-C). Interestingly, a greater decrease in the number of HSPC in mice treated with miR-142a inhibitors was observed (FIGS.29B-C). Such downregulation in hematopoiesis mirrored an observed decrease in CD11b+ cells, Ly6Chi monocytes, and neutrophils in the circulation of these mice, with miR-142a inhibitors exerting a more profound effect (FIGS.29D-E). Together, these data show that apoE expression plays a role in dictating the capacity of macrophage- derived exosomes to suppress hyperlipidemia-driven hematopoiesis and myelopoiesis via the regulation of miR-146a-5p and miR-142a-3p in recipient cells. Loss of apoE expression in macrophages results in exosomes that drive the proliferation, activation, and production of IFN-γ in T lymphocytes. In view of the data shown in FIGS.26A-F demonstrating a capacity for EKO-BMDM- exo to drive the activation and proliferation of CD4+ T cells in vitro, it was investigated whether infusions of these exosomes into hyperlipidemic WD-fed AAV8-PCSK9 mice could adversely impact the activity of T lymphocytes in these mice. Interestingly, mice that received EKO- BMDM-exo infusions for 4 weeks displayed elevated levels of circulating T lymphocytes (CD45+ CD3e+) when compared to those that received WT-BMDM-exo or PBS (FIGS.30A- B), while no differences were noted for circulating B lymphocytes (CD45+ B220+) (FIGS.30A- B). Consistent with these findings in the circulation, an accumulation of CD4+ and CD8+ T lymphocytes was also observed in the spleens of mice infused with EKO-BMDM-exo (FIGS. 30C-D). Moreover, these cells exhibited increased cell-surface levels of CD69 (FIGS.30C and E), an established marker for recently activated T lymphocytes (Cibrian D, and Sanchez-Madrid F. Eur J Immunol.2017;47(6):946-53). These findings are consistent with the data in FIGS.30C and F-G, which uncovered greater levels of effector memory cells T cells (TEM, CD44hi CD62Llo) and lower levels of naïve T cells (Tnaive, CD44lo CD62Lhi) in both splenic CD4+ and CD8+ populations derived from mice infused with EKO-BMDM-exo. Furthermore, these mice exhibited increased levels of splenic CD44+ CD4+ and CD44+ CD8+ T lymphocytes expressing the activation marker and chemokine receptor C-X-C Motif Chemokine Receptor 3 (CXCR3) (FIGS.30C and H), which participates in modulating T lymphocyte activation and trafficking (Groom JR, and Luster AD. Exp Cell Res.2011;317(5):620-31). Next, the impact of macrophage exosomes on regulating the production of IFN-γ, a pro- inflammatory cytokine associated with helper T cell type I (Th1) and cytotoxic T cell type I (Tc1), in splenic CD4+ and CD8+ T lymphocytes that had been stimulated with 20 ng/mL of phorbol 12-myristate 13-acetate (Zhang S, et al. Cell Metab.2019;29(2):443-56 e5) and 1 µg/mL of ionomycin for 4 hours was detected. Consistent with the in vitro data in FIG.26F, our ex vivo data in FIGS.30I-J show that levels of IFN-γ+ cells derived from the spleens of mice infused with EKO-BMDM-exo increased by 33% and 44% among CD4+ and CD8+ populations, respectively, as compared to T cells examined from WD-fed AAV8-PCSK9 mice infused with either WT-BMDM-exo or PBS. Furthermore, these cells displayed 41% and 45% greater MFI for IFN-γ among CD4+ and CD8+ populations, respectively, as compared to cells derived from mice infused with WT-BMDM-exo and PBS (FIGS.30I-J). Lastly, it was assessed whether systemic infusions of miR-146a mimics or miR-142a inhibitors could reverse T lymphocyte activation in hyperlipidemic WD-fed Apoe-/- mice. While such treatments did not change total numbers of lymph node-derived CD4+ and CD8+ T lymphocytes (FIG.30K), they did suppress the expression of the activation marker CD69 in both CD4+ and CD8+ T lymphocyte populations (FIG.30L). Furthermore, both treatments successfully lowered levels of the TEM subset while elevating levels of the Tnaive subset in both CD4+ and CD8+ T lymphocytes (FIGS.30M-N). Treatments with both forms of RNA oligonucleotides also suppressed the levels of CD44+ CD4+ and CD44+ CD8+ T lymphocytes expressing CXCR3 (FIG.30O). Interestingly, miR-146a mimics exerted a more profound effect in reducing T lymphocyte activation and trafficking (FIGS.30K-O). Collectively, findings from this study demonstrate that macrophage apoE expression controls hyperlipidemia-driven innate and adaptive immunity and inflammation via their secreted exosomes. The expression of ApoE by myeloid cells has long been recognized to serve as a source of immune regulation (Mahley RW. Science.1988;240(4852):622-30; Curtiss LK, and Boisvert WA. Curr Opin Lipidol.2000;11(3):243-51; and Linton MF, et al. Science. 1995;267(5200):1034-7). Beyond contributing to the pool of apoE in plasma that benefits liver- mediated remnant lipoprotein clearance (Mahley RW, and Ji ZS. J Lipid Res.1999;40(1):1-16), apoE expression by myeloid cells has the ability to exert both cell-intrinsic and cell-extrinsic properties that together shape the immune repertoire and inflammatory status of leukocytes in hyperlipidemia (Davignon J. Arterioscler Thromb Vasc Biol.2005;25(2):267-9). Findings from this study provide evidence for an immune-regulatory property for macrophage apoE expression. The data show that apoE expression by macrophages is important for their ability to communicate immunometabolic signaling to recipient cells via exosomes. While the expression of apoE did not impact the size or number of exosomes produced by cultured primary macrophages, it substantially altered their capacity to communicate immunometabolic signaling to myeloid cells, T lymphocytes, and HSPCs. Indeed, the loss of apoE expression in macrophages led to the production of EKO-BMDM-exo that promoted the maturation of BMDC, primed BMDM to become more susceptible to inflammatory signaling, fostered pro-survival and inflammatory signaling in T lymphocytes, and drove hematopoiesis in mice with hyperlipidemia. Furthermore, beyond impacting the production of inflammatory cytokines, EKO-BMDM-exo substantially impaired an important anti-inflammatory process in recipient macrophages. By downregulating cell-surface levels of MerTK in naïve cultured macrophages, EKO-BMDM-exo decreased their phagocytic uptake of apoptotic cells, hampering a process recognized for augmenting tissue repair and anti-inflammatory properties (Thorp E, et al. Arterioscler Thromb Vasc Biol.2008;28(8):1421-8; Zhang S, et al. Cell Metab. 2019;29(2):443-56 e5; and Yurdagul A, Jr., et al. Front Cardiovasc Med.2017;4(86). The role for apoE in serving as a checkpoint against inflammatory exosome production by macrophages is supported by numerous lines of evidence. Exposure to WT-BMDM-exo attenuated the expression of inflammatory cytokines in BMDM and the maturation of BMDC in response to Toll-like receptor (TLR) signaling following LPS stimulation. It also enhanced cell- surface MerTK levels and improved the phagocytic capacity of recipient naïve BMDM. The findings also identify apoE as molecular cargo in macrophage exosomes that could account for an observed enrichment of apoE in recipient macrophages, which has been shown to serve a functional role in improving their anti-inflammatory activity (Curtiss LK, and Boisvert WA. Curr Opin Lipidol.2000;11(3):243-51). Conversely, the apoE-depleting effect, caused by EKO- BMDM-exo exposure to recipient macrophages, could account for the observed heightened inflammatory properties. This effect is akin to that of IFN-γ signaling that reduces apoE levels in macrophages polarizing the cells into an inflammatory phenotype (Brand K, et al. J Clin Invest. 1993;91(5):2031-9). Interestingly, the modulation of cellular apoE levels by cytokine signaling was reported to occur through post-translational mechanisms (Brand K, et al. J Clin Invest. 1993;91(5):2031-9). Similar mechanisms could explain the observations of reduced apoE levels in BMDM stimulated with EKO-BMDM-exo. In contrast, increased apoE levels in BMDM stimulated with WT-BMDM-exo could have derived from a direct delivery of apoE as exosomal cargo, as no changes in apoE mRNA were detected in the recipient cells. It is interesting to speculate on the functional consequences conferred by the modulation of cellular apoE levels by the two forms of BMDM exosomes. Robust changes in cellular apoE levels could have directly contributed to driving bioenergetic fuel utilization, lipid homeostasis, redox stress, and microRNA modulation in recipient macrophages. Support for this idea stems from the observations demonstrating the ability for endogenous apoE levels to upregulate levels of miR-146a-5p (Li K, et al. Circ Res.2015;117(1):e1-e11) while simultaneously downregulating miR-142a-3p levels in myeloid cells and their progenitors (Phu et al.). The reciprocal control in levels of these two microRNAs by cellular apoE expression favored mitochondrial metabolism by fostering FAO and OxPHOS over glycolysis, resulting in suppressed myeloid cell activation, hyperlipidemia-driven inflammation and hematopoiesis (Phu et al.). Together, the findings show that the modulation of apoE levels in macrophages serves as a rheostat for the production of exosomes capable of communicating a spectrum of immunometabolic-regulatory properties. A downregulation of cellular apoE levels caused by inflammatory cytokine signaling (Brand K, et al. J Clin Invest.1993;91(5):2031-9) likely polarizes cells to produce exosomes that serve to drive glycolytic metabolism in recipient leukocytes to exacerbate inflammation. Conversely, an upregulation of apoE levels, such as in response to interleukin-4-stimulated PPARγ signaling (Kidani Y, and Bensinger SJ. Immunol Rev.2012;249(1):72-83; and Daniel B, et al. Nucleic Acids Res.2018;46(9):4425-39) that benefits cellular cholesterol efflux), also results in the production of exosomes that communicate anti-inflammatory and pro-resolution signaling as reported in the studies of macrophages exposed to this cytokine (Bouchareychas L, et al. Cell Rep.2020;32(2):107881; and Phu TA, et al. Mol Ther.2022;30(6):2274-97). In line with such reasoning, ongoing studies are underway to determine whether apoE expression is required for the production of macrophage exosomes with potent anti-inflammatory properties following interleukin-4 treatment. Results of such studies could provide new insight to account for observations reporting impaired intercellular communication by exosomes produced from apoE-deficient M2-like macrophages in a model of tumor cell metastasis (Zheng P, et al. Cell Death Dis.2018;9(4):434). While bioactive cargo associated with macrophage exosomes beyond identifying apoE in WT-BMDM-exo was not studied, mechanisms responsible for their differential signaling properties when produced by Apoe-/- or wildtype macrophages were identified. Pro- inflammatory properties displayed by EKO-BMDM-exo were found to derive from their ability to upregulate cellular aerobic glycolytic metabolism through the increase of GLUT1-mediated glucose uptake upon LPS-stimulation. EKO-BMDM-exo communicated this metabolic property by suppressing miR-146a-5p levels that we had previously demonstrated to be controlled by apoE expression (Li K, et al. Circ Res.2015;117(1):e1-e11). These findings show that a paucity of miR-146a-5p levels seen in apoE-deficient BMDM can be communicated to naïve wildtype macrophage via exosomes to drive NF-κB signaling, thereby increasing GLUT1-driven immune cell activation (Obaid M, et al. Sci Rep.2021;11(1):232). Furthermore, beyond facilitating the uptake of glucose in naïve macrophages, that in itself is insufficient to drive inflammatory gene activation (Nishizawa T, et al. Cell Rep.2014;7(2):356-65), EKO-BMDM-exo robustly upregulated the expression of numerous glycolytic genes to accentuate aerobic glycolysis. Whether such complex bioenergetic polarization resulted from reduced cellular apoE levels alone, or if additional molecular cargo delivered by EKO-BMDM-exo contributed to the effects, is unclear and are topics of ongoing investigations. In marked contrast, while WT-BMDM-exo exerted a modest increase in glycolytic function in recipient naïve wildtype macrophages, they exerted a profound increase in OxPHOS that was absent in cells treated with EKO-BMDM-exo. These observations are consistent with findings showing that macrophage exosome function revealing their capacity to resolve inflammatory immune cell activation (Bouchareychas L, et al. Cell Rep.2020;32(2):107881; and Phu TA, et al. Mol Ther.2022;30(6):2274-97). Such reciprocal modulation of OxPHOS in recipient macrophages correlated with an upregulation of the mitochondrial fatty acid transporter CPT1A in cells treated with WT-BMDM-exo and its downregulation in those treated with EKO- BMDM-exo. A mechanism to explain this opposing mode of bioenergetic control is centered on the capacity for WT-BMDM-exo to reduce miR-142a-3p levels in recipient cells, a process we recently uncovered to be dependent on cellular apoE expression. Further support for the involvement of these two microRNA-signaling axes as central to apoE control of macrophage exosome activity in the regulation of immunometabolism and inflammation derived from in vivo rescue experiments in which miR-146a mimics or miR-142a inhibitors were infused into hyperlipidemic Apoe-/- mice. Irrespective of the exact mode of cellular signaling conferred by the two forms of exosomes, unbiased RNA-seq and gene ontology assessments revealed their distinct capacity to modulate the expression levels of genes associated with inflammation and its resolution. Among these pathways responsible for oxidative stress control include selenoproteins and glutathione peroxidases, ABC lipid transporters, and genes mediating phagocytosis. Consistent with these findings, a broad array of functional assays performed in this study revealed the capacity of EKO-BMDM-exo to drive neutral lipid accumulation and impair the phagocytic uptake of apoptotic cells in naïve macrophages. These assays also identified the capacity of EKO-BMDM- exo to increase both cellular and mitochondrial oxidant stress, which augmented the opening of the mitochondrial pore. Such effects likely contributed to impair mitochondrial activity, detected in recipient cells as decreases in membrane potential and levels of the reduced form of glutathione that mediates oxidative stress control. Together, such deleterious properties conferred by EKO-BMDM-exo unveil new insights that extend earlier observations of myeloid apoE expression in regulating cellular responses to redox stress (Igel E, et al. J Biol Chem. 2021;297(3):101106). Furthermore, the study reports evidence for macrophage apoE expression acting in a paracrine manner through WT-BMDM-exo to profoundly oppose cellular and mitochondrial redox stress, while improving mitochondrial function by driving fatty acid utilization and OxPHOS in recipient myeloid cells. Together, the results disclosed herein show that cellular apoE expression in macrophages can communicate immunometabolic benefits via exosomes to neighboring cells and those at a distance. Their functional targets included mature leukocytes in the circulation and lymphoid tissues, as well as their progenitor stem cells in the bone marrow and the spleen to control hematopoiesis. Based on these observations, chronic inflammatory disorders including hyperlipidemia and diabetes, macrophage exosomes could serve to reinforce deleterious leukocytosis and leukocyte activation to accelerate the pathogenesis of atherosclerosis. In contrast, in situations of plasma lipid control and PPARγ signaling, macrophage exosomes could serve as a negative feedback loop to control hematopoiesis and actively stimulate the resolution of inflammation. This could include functions such as driving the phagocytic clearance of apoptotic cells and restoring positive cellular lipid efflux in atheroma, which are both recognized as important mechanisms responsible for driving lesion stabilization in human coronary artery disease (Doran AC, et al. Nat Rev Immunol.2020;20(4):254-67). Furthermore, macrophage exosomes could also serve as a source of cardiovascular protection by controlling metabolic signaling in other cell types, including adipocytes to regulate the production of adipokines, thereby controlling insulin sensitivity and obesity (Phu TA, et al. Mol Ther.2022;30(6):2274- 97). Together, these findings provide evidence of macrophage exosomes, and the contribution of isoform-specific apoE expression, for their differential role as mediators of immunometabolic communication in cardiometabolic disease. Materials and methods. Animal studies. In vivo studies were conducted using C57BL/6J mice intravenously injected with AAV8-PCSK9. Six-week-old male AAV8-PCSK9-injected C57BL/6 wildtype mice were fed a Western diet (Research Diets, USA) for 2 weeks before being randomly assigned to be infused with EKO-BMDM-exo, WT-BMDM-exo, or PBS as control for 4 weeks while remaining on the Western diet for the duration of the study (n = 4-5 for each treatment group). For RNA oligonucleotide infusions, six-week-old male Apoe-/- mice were fed a Western diet (Research Diets, USA) for 2 weeks before being randomly assigned to be infused i.v. with 1 nmol of miR-146a mimics, miR-142a inhibitors, or negative control RNA (scrambled) twice a week for a total of four weeks while remaining on Western diet (Research Diets, USA) (Li K, et al. Circ Res.2015;117(1):e1-e11; and Sun X, et al. Circ Res.2014;114(1):32-40). Briefly, 1 µl of 1 nmol/ µl antisense oligonucleotides targeting miR-142a (miR-142a inhibitors), miR-146a mimics, or negative control (Thermo Fisher, USA) was mixed with 100 µl PBS (Corning, USA). The transfection reagent was prepared by mixing 30 µl Lipofectamine RNAiMAX (Thermo Fisher, USA) with 70 µl PBS (Corning, USA). The 100 µl of oligonucleotides + PBS mixture was subsequently mixed with the 100 µl transfection reagent to create a 200 µl final mixture by pipetting 100x. This mixture was infused i.v. to WD-fed Apoe-/- mice via retro-orbital injection twice a week (1 nmol/mouse/injection). For bone marrow derived macrophage (BMDM) exosome collection, bone marrow cells were collected from age-matched 6- to 12-week-old male Apoe-/- or wildtype mice on C57BL/6J background. These cells were then differentiated into macrophages prior to exosome collection. Detailed elaboration of the cell culture and exosome isolation methods are described herein. Data collection and analyses were conducted in a blinded-fashion. Mice were housed and bred in specific pathogen–free conditions. Cell culture. Murine BMDM were obtained (Bouchareychas L, et al. Cell Rep. 2020;32(2):107881; Bouchareychas L, et al. iScience.2021;24(8):102847; and Phu TA, et al. Mol Ther.2022;30(6):2274-97). Briefly, bone marrow cells were flushed from the tibia and femurs of age-matched 6- to 12-week-old male Apoe-/- or wildtype mice on C57BL/6J background. Cells were cultured in complete media containing DMEM (Corning, USA) supplemented with 10% fetal bovine serum (GIBCO, USA), 1% GlutaMax (GIBCO, USA), and 1% penicillin-streptomycin (GIBCO, USA) and differentiated with 25 ng/ml mouse M-CSF (Peprotech, USA) for 6 days in 37°C and 5% CO₂. Cells were then cultured in exosome-free media for the production and isolation of exosomes. For in vitro experiments, BMDM were seeded into 12-well culture plates (Corning, USA) at a concentration of 3 x 10⁵ cells/well and treated with 2 x 10⁹ particles/mL of exosomes or equal volume of PBS for 18 hours. The cells were then collected for analysis or stimulated with lipopolysaccharides (LPS) (Sigma Aldrich, USA) for 6 hours. For bone marrow derived dendritic cells (BMDC), bone marrow cells were flushed from the tibia and femurs of 6- to 12-week-old male Apoe-/- or wildtype mice on C57BL/6J background. Cells were cultured in complete media and differentiated with 25 ng/ml mouse GM-CSF (Peprotech, USA) for 6 days in 37°C and 5% CO2. Cells were collected in media suspension as immature BMDC. Cells were then seeded into 12-well culture plates (Corning, USA) at a concentration of 3 x 10⁵ cells/well and treated with 2 x 10⁹ particles/mL of exosomes or equal volume of PBS for 18 hours. The cells were then collected for analysis or stimulated with lipopolysaccharides (LPS) (Sigma Aldrich, USA) for 6 hours. BMDM exosome isolation and nanoparticle tracking analysis. The exosome isolation and characterizations were performed in adherence to the MISEV2018 guidelines (Thery C, et al. J Extracell Vesicles.2018;7(1):1535750). BMDM were seeded into 15-cm plates (Corning, USA) at a density of 5 x 10⁶ cells/plate as described above.25 ng/ml mouse M-CSF (Peprotech, USA) was added every 2 days for 6 days. The cells were then washed twice with PBS (Corning, USA) and cultured in exosome-depleted media prepared by ultracentrifugation for 18 hours at 100,000 x g (Type 45 Ti rotor, Beckman Coulter, USA) and filtration (0.2 µm). After 24 hours of incubation, the conditioned media was collected. Exosomes were isolated from conditioned media using Cushioned-Density Gradient Ultracentrifugation (C-DGUC) (Duong P, et al. PLoS One.2019;14(4):e0215324). Briefly, the conditioned media was centrifuged at 400 x g for 10 min at 4°C to pellet dead cells and debris followed by centrifugation at 2000 x g for 20 min at 4°C to eliminate debris and larger vesicles. The supernatant was then filtered (0.2 µm) and centrifuged on a 60% iodixanol cushion (Sigma-Aldrich, USA) at 100,000 x g for 3 hours (Type 45 Ti, Beckman Coulter, USA). OptiPrep density gradient (5%, 10%, 20% w/v iodixanol) was employed to further purify the exosomes at 100,000 x g for 18 hours at 4°C (SW 40 Ti rotor, Beckman Coulter, USA). Afterwards, twelve 1 mL fractions were collected starting from the top of the tube. Fraction 7 of the gradient was dialyzed in PBS with the Slide-A-Lyzer MINI Dialysis Device (Thermo Fisher Scientific, USA) and used for subsequent experiments and analyses. Particles in Fraction 7 were subjected to size and concentration measurement by NanoSight LM14 (Malvern Instruments, Westborough, USA) at a 488-nm detection wavelength. The analysis settings were optimized and kept identical for each sample. With a detection threshold set at 3, three videos of 1 min each were analyzed to give the mean, mode, median, and estimated concentration for each particle size. Samples were diluted in 1:100 or 1:200 PBS and measured in triplicates. Data were analyzed with the NTA 3.2 software. The exosome samples were store at 4°C and used within one month after isolation. Details relevant to exosome isolation and physical characterization data have been submitted to the EV-TRACK knowledgebase (EV-TRACK ID: EV220298). Labeling and in vitro/in vivo tracking of BMDM exosomes. Fluorescently detectable BMDM exosomes were generated using PKH26 (Sigma-Aldrich, USA) or DiR (DiIC18(7) (1,1’-Dioctadecyl-3,3,3′,3′ Tetramethylindotricarbocyanine Iodide) (Invitrogen, USA). The dye was added to the 3 mL iodixanol cushion layer containing exosome or to 3ml of PBS to achieve a final concentration of 3.5 mM for PKH26 or 1 μM for DiR and incubated for 20 min at room temperature. Labeled exosomes and control were loaded below an iodixanol step gradient as described above in the exosome isolation section. Free dye and non-specific protein-associated dye were eliminated from labeled exosomes or from PBS control during this separation step. For in vitro experiments, naïve wildtype BMDM were exposed to 2 x 10⁹ PKH26-labeled exosome for two hours, washed three times with PBS and imaged using a Zeiss Observer microscope. Fluorescence intensity of the PKH26-positive cells was measured by using ImageJ. For in vivo experiments, 10-week-old Western diet-fed AAV8-PCSK9-injected mice were infused i.p. with PBS or 1 x 10¹⁰ DiR-labeled EKO-BMDM-exo or WT-BMDM-exo for six hours. The mice were then extensively perfused with PBS. Blood, aortas, hearts, livers, eWAT, bones, spleen, lungs, brains, intestines, and kidneys were collected, imaged, and quantified for DiR fluorescence signal using the Odyssey Infrared Imaging System and Image Studio software. Transmission electron microscopy. Exosome morphology was assessed by Electron microscopy by loading 7 x 10⁸ exosomes onto a glow discharged 400 mesh Formvar-coated copper grid (Electron Microscopy Sciences, USA). The nanoparticles were left to settle for two minutes, then the grids were washed four times with 1% Uranyl acetate. Excess Uranyl acetate was blotted off with filter paper. Grids were then allowed to dry and subsequently imaged at 120kV using a Tecnai 12 Transmission Electron Microscope (FEI, USA). Protein extraction and immunoblotting. Each fraction of the C-DGUC purified exosomes (37.5 µL sample) was mixed with 12.5 mL of 4x Laemmli buffer (Bio-Rad, USA). For cell lysates, cells were lysed in RIPA Buffer (Cell Signaling, USA) containing cOmplete, Mini, EDTA-free Protease Inhibitor Cocktail (Roche, Switzerland) and 1 mM PMSF (Cell Signaling, USA). Protein concentrations were measured using Pierce BCA Protein Assay Kit (Thermo Fisher Scientific, USA). A total of 15 ug of proteins was diluted with PBS to 37.5 µL, then mixed with 12.5 µL 4x Laemmli buffer (Bio-Rad, USA). Samples were subsequently heated at 95°C for 5 minutes. Samples were then loaded on a 10% SDS-PAGE gel and transferred onto a PVDF membrane (Bio-Rad, USA). The membranes were blocked with 5% non-fat milk dissolved in PBS for one hour and then incubated with primary antibodies overnight at 4°C. Primary antibodies for exosome markers include anti-CD9 (1:100, BD Biosciences, USA), anti- CD63 (1:100, BD Biosciences, USA), and anti-CD81 (1:100, Santa Cruz, USA), and anti-apoE (1:1000) (Raffai RL, et al. Proc Natl Acad Sci U S A.2001;98(20):11587-91). Primary antibodies for cell lysate include anti-Calnexin (1:500, Abcam, USA), anti-GM130 (1:250, BD Biosciences, USA), anti-CPT1A (1:200, Santa Cruz, USA), anti-apoE (1:1000) (Raffai RL, et al. Proc Natl Acad Sci U S A.2001;98(20):11587-91), anti-GAPDH (1:1000, Cell Signaling, USA), and anti-b-Actin (1:1000, Abcam, USA). After 4 washes in PBS containing 0.1% Tween (PBST), membranes were incubated with corresponding HRP-conjugated secondary antibodies: anti-Mouse IgG-HRP (1:1000, Santa Cruz, USA) or anti-Rabbit IgG-HRP (1:1000, Thermo Fisher Scientific, USA) for 1 hour and washed in PBST. Signals were visualized after incubation with Amersham ECL Prime substrate and imaged using an ImageQuant LAS 4000. Quantification was analyzed using ImageJ. RNA extraction and gene expression analysis using qRT-PCR. Total RNA isolated from cells was extracted using Qiazol Lysis Buffer (QIAGEN, Germany) and purified using the RNeasy Mini Kit (QIAGEN, Germany) according to the manufacturer’s protocol. RNA was quantified using Nanodrop (Thermo Fisher Scientific, USA) and reverse transcribed using the iScript Reverse Transcription Supermix (Bio-Rad, USA) for mRNA or the miRCURY LNA RT Kit (QIAGEN, Germany) for microRNA analysis. qPCR reactions were performed using the Fast SYBR Green Master Mix (Applied Biosystems, USA) for mRNA or the miRCURY LNA SYBR Green PCR Kit (QIAGEN, Germany) for microRNA and processed using a QuantStudio 7 Flex Real-Time PCR System. Ct values were normalized to the housekeeping genes Gapdh and B2m. For microRNA expression, UniSp6 was used as a spike-in control while U6 snRNA and miR-16-5p (QIAGEN, Germany) were used as reference genes. The reactions were done in triplicates. Whole transcriptome library preparation, sequencing, and analysis. Total RNA isolated from cells was extracted using Qiazol Lysis Buffer (QIAGEN, Germany) and purified using the RNeasy Mini Kit (QIAGEN, Germany) according to the manufacturer’s protocol. Isolated RNA sample was then DNase treated with TURBO DNA-free (Thermo Fisher), then purified and concentrated with Zymo RNA Clean & Concentrator – 5 (Zymo Research). The RNA was measured for quantity with Quant-iT Ribogreen RNA Assay (Thermo Fisher) and quality with Agilent High Sensitivity RNA Screen Tape and buffer (Agilent). For mouse RNA samples, an indexed, Illumina-compatible, double-stranded cDNA whole transcriptome library was synthesized from 10ng of total RNA with Takara Bio’s SMARTer Stranded Total RNA-Seq kit v2 Pico Input Mammalian (Takara Bio) and SMARTer RNA Unique Dual Index Kit (Takara Bio). Library preparation included RNA fragmentation (94°C for 4 min), cDNA synthesis, a 5- cycle indexing PCR, ribosomal cDNA depletion, and a 12-cycle enrichment PCR. Each library was measured for size with Agilent’s High Sensitivity D1000 ScreenTape and reagents (Agilent) and concentration with KAPA SYBR FAST Universal qPCR Kit (Kapa Biosystems). Libraries were then combined into an equimolar pool which was also measured for size and concentration. The pool was clustered onto a flowcell (Illumina) with a 1% v/v PhiX Control v3 spike-in (Illumina) and sequenced on Illumina’s NovaSeq 6000 at a final flowcell concentration of 400pM. The first and second reads were each 100 bases. For data processing, the SMARTer Total RNA pico v2 reads are quality filtered and trimmed as recommended by Takara Bio with the removal of the first 3 bases of read2. After trimming and filtering reads are genome and transcriptome mapped using STAR (v.2.5.3a). Aligned BAM files are converted into gene counts matrices for further analysis using FeatureCounts (v.2.0.1), using read2 as the sense strand. For RNAseq analysis, differential expression was conducted using the DESeq2 package (version 1.20.0) in R (version 3.5.0) for the gene expression analyses. The raw read counts for the samples were normalized using the median ratio method (default in DESeq2). The significant differentially expressed genes (by Benjamini-Hochberg adjusted p values) are reported in the paper. Heatmaps were created using the pheatmap (v.1.0.10) package in R. GO analyses were performed using PANTHER GO-slim Biological Process and DAVID with an FDR threshold at ≤ 0.05. Phagocytotic uptake of CFSE-labeled apoptotic cells. Naïve wildtype BMDM were seeded at a density of 1 x 10⁶ cells/well in a 6-well culture plate and treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. The next day, BMDM were treated with 3 x 10⁶ Jurkat cells that had undergone UV-induced apoptosis for 50 minutes and labeled with CFSE. BMDM were then washed three times with PBS and dissociated from the cell culture plates. The cells were then assessed for the uptake of CFSE- labeled apoptotic Jurkat cells using a Beckman CytoFLEX S cytometer (Beckman Coulter, USA). In vitro CD4+ T lymphocyte activation assay and IFN-γ detection. Naive splenic CD4+ T lymphocytes were captured using negative selection magnetic beads (Miltenyi Biotec, Germany). These cells were stimulated with αCD3/αCD28 beads (Thermo Fisher, USA) and 5 ng/ml of recombinant murine IL-2 (Peprotech, USA) for 48 hours while also being co-cultured with 2 x 10⁹ particles/mL of EKO-BMDM-exo, or WT-BMDM-exo, or PBS. Measurements of T lymphocyte activation were assessed using flow cytometric detection of CD69 and CD25. For detection of IFN-γ, naive splenic CD4+ T lymphocytes were stimulated with αCD3/αCD28 beads (Thermo Fisher, USA) and 5 ng/ml of recombinant murine IL-2 (Peprotech, USA) for 12 hours while also being co-cultured with 2 x 10⁹ particles/mL of EKO-BMDM-exo, or WT- BMDM-exo, or PBS. Cells were cultured in the presence of the Protein Transport Inhibitor cocktail (Invitrogen, USA). They were then permeabilized using the Foxp3/Transcription Factor Staining Buffer Set (eBioscience, USA) and stained with anti-IFNγ (clone XMG1.2) at 1:100 concentration for 60 min in room temperature according to the manufacturer’s protocol. Glucose uptake assay in cultured macrophages and circulating monocytes. BMDM were seeded at a density of 150,000 cells/well in a 24-well culture plate and treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS for 18 hours. The next day, BMDM were stimulated with 100 ng/mL LPS for 6 hours. The cells were then preincubated with KRPH buffer containing 2% bovine serum albumin, 20 mM HEPES, 5 mM KH2PO4, 1 mM MgSO4, 1 mM CaCl2, 136 mM NaCl, and 4.7 mM KCl, pH 7.4 (all from Sigma Aldrich, USA) for 40 minutes. Subsequently, 10 µL/well of 10 mM 2-deoxyglucose (2-DG) was added and incubated for 20 minutes. Next, cells were washed 3x with PBS to remove exogenous 2-DG. BMDM were then lysed and 2-DG uptake was processed using a Glucose Uptake Assay Kit (Abcam, USA) according to the manufacturer’s protocol. Absorbance reading was measured at OD 412 nm on a microplate reader (Molecular Devices, USA). For 2-NBDG uptake, pre-stained circulating Ly6Chi monocytes were incubated with 2-NBDG (Invitrogen, USA) for 30 min in 37C with 5% CO₂. The cells were then washed with PBS and analyzed for 2-NBDG uptake using a CytoFLEX S cytometer (Beckman, USA). Assessments of glutathione levels, neutral lipids accumulation, oxidative stress, and mitochondrial health in cultured macrophages and circulating monocytes. Measurements of glutathione levels and GSH:GSSG ratio in BMDM were conducted using the GSH/GSSG Ratio Detection Assay Kit (Abcam, USA). BMDM were plated at a density of 1 x 10⁶ cells/well in a 6-well plate and treated with 2 x 10⁹ particles/mL of EKO-BMDM-exo, WT-BMDM-exo, or PBS as control for 18 hours. Cells were then washed twice with PBS (Corning, USA) and lysed with the kit’s Mammalian Lysis Buffer (Abcam, USA). Measurements of total glutathione and GSH levels were conducted using the manufacturer’s protocol. For analysis of neutral lipids accumulation, BMDM or pre-stained circulating Ly6Chi monocytes were stained with LipidTOX (Invitrogen, USA) (1:250) for 30 minutes in room temperature and analyzed using a CytoFLEX S cytometer (Beckman, USA). For analysis of cellular oxidative stress, BMDM or pre-stained circulating Ly6Chi monocytes were stained with CellROX (Invitrogen, USA) (5 μM) for 30 minutes at 37°C. Cells were then analyzed using a CytoFLEX S cytometer (Beckman, USA). For analysis of mitochondrial health and functions, BMDM or pre-stained circulating Ly6Chi monocytes were stained with MitoSOX (Thermo Fisher, USA) or TMRM (Thermo Fisher, USA) at final concentrations of 5 μM and 0.1 μM, respectively. The cells were then incubated in 37°C for 30 minutes. Cells were then analyzed using a CytoFLEX S cytometer (Beckman, USA). To measure mitochondrial transition pore opening, BMDM were analyzed using the MitoProbe Transition Pore Assay Kit (Invitrogen, USA) according to the manufacturer’s protocol. Briefly, cell suspensions were mixed with 2 µM Calcein AM and 160 µM CoCl₂. For negative control, cells were also mixed with 0.2 µM ionomycin. Cells were then analyzed for mitochondrial Calcein AM retention using the CytoFLEX S cytometer (Beckman, USA). Multiplex immunoassay analysis of cytokines production. Total splenic cells or bone marrow cells were plated at 900,000 cells/well in a 6-well plate and stimulated with 100 ng/mL LPS for 6 hours. The conditioned media was then collected and spun at 400 x g for 10 minutes to remove the cells. TNF-α, IL-6, and IL-1β cytokine levels in the conditioned media were measured using the V-Plex Mouse Custom Cytokine Kit (Meso Scale Discovery, USA) according to the manufacturer’s protocol. Plasma cytokines (TNF-α, IFN-γ, IL-6, and IL-1β) were also measured using the V-Plex Mouse Custom Cytokine Kit (Meso Scale Discovery, USA) according to the manufacturer’s protocol. Measurements of lactate production by cells. BMDM were plated at 900,000 cells/well in a 6-well plate and treated with exosomes for 18 hours. Cells were then either unstimulated or stimulated with 100 ng/mL LPS for 6 hours. The conditioned media was then collected and spun at 400 x g for 10 minutes to remove the cells. The lactate levels in these conditioned media were measured using the L-Lactate Colorimetric Assay Kit (Abcam, USA) according to the manufacturer’s protocol. Absorbance reading was measured at OD 450 nm on a microplate reader (Molecular Devices, USA). Assessments of leukocyte numbers and cellular markers using flow cytometry. Mice were anesthetized with isoflurane (Forane, Baxter, USA) and peripheral blood was collected by retro- orbital bleeding with heparinized micro-hematocrit capillary (Fisher Scientific, USA) in tubes containing 0.5M EDTA. Red blood cells were lysed in RBC lysis buffer (BioLegend, USA). Nonspecific binding was blocked with TruStain FcX Ab (BioLegend, USA) for 10 min at 4°C in FACS buffer (Ca²⁺/Mg²⁺-free PBS with 2% FBS and 0.5 mM EDTA) before staining with appropriate Abs: CD11b (clone M1/70), Ly-6C (clone HK1.4), CD115 (clone AFS98), and CD45 (clone 30-F11) (all BioLegend, USA) for 30 min at 4°C. The antibody dilutions ranged from 1:200 to 1:100. Splenocytes were isolated using mechanical dissociation. Briefly, spleens were mashed using the bottom of a 3 mL syringe (BD Biosciences). The cells were then passed through a 70 µm cell strainer and incubated in RBC lysis buffer (BioLegend, USA). Nonspecific binding was blocked with TruStain FcX Ab (BioLegend, USA) for 10 min at 4°C in FACS buffer before staining with appropriate Abs: CD11b (clone M1/70), Ly-6C (clone HK1.4), Ly-6G (clone 1A8), and CD11c (clone N418). Splenic dendritic cells were analyzed using the following Abs panel: CD11b (clone M1/70), Ly-6C (clone HK1.4), CD11c (clone N418), I-A/I-E (clone M5/114.15.2). Splenic T lymphocytes were analyzed using the following Abs panel: CD4 (clone RM4-5), CD8a (clone 53-6.7), CXCR3 (clone CXCR3-173), CD69 (clone H1.2F3), CD62L (clone MEL-14), and CD44 (clone IM7). The antibody dilutions ranged from 1:200 to 1:100. Lymph node-derived cells were collected from the inguinal, mesenteric, axillary, and mediastinal lymph nodes. The cells were then passed through a 70 µm cell strainer and incubated in RBC lysis buffer (BioLegend, USA). T lymphocytes were analyzed using the following Abs panel: CD4 (clone RM4-5), CD8a (clone 53-6.7), CXCR3 (clone CXCR3-173), CD69 (clone H1.2F3), CD62L (clone MEL-14), and CD44 (clone IM7). The antibody dilutions ranged from 1:200 to 1:100. For detection of GLUT1 on cellular surface, BMDM were incubated with anti-GLUT1 (clone SA0377) at 1:50 concentration in FACS buffer for 30 min in 4°C. Cells were then washed once with PBS and incubated with APC-conjugated Goat anti-Rabbit (1:200 concentration) in FACS buffer for 30 min in 4°C. For analysis of nuclear NF-κB activity, the nuclei of BMDM were permeabilized using the Foxp3/Transcription Factor Staining Buffer Set (eBioscience, USA) and stained with anti-phospho-p65 subunit (clone 93H1) at 1:100 concentration for 60 min in room temperature according to the manufacturer’s protocol. For intracellular cytokine staining, 2 x 10⁶ splenocytes were cultured in 1 µg/mL ionomycin (Sigma Aldrich, USA), 20 ng/mL phorbol 12-myristate 13-acetate (51) (Fisher Scientific, USA), and Protein Transport Inhibitor cocktail (Invitrogen, USA) for 4 hours. The cells were then collected and stained with anti-CD4 (clone RM4-5), anti-CD8a (clone 53-6.7), anti-CXCR3 (clone CXCR3-173). Cells were then permeabilized using the Foxp3/Transcription Factor Staining Buffer Set (eBioscience, USA) and stained with anti-IFNγ (clone XMG1.2) at 1:100 concentration for 60 min in room temperature according to the manufacturer’s protocol. The flow cytometry experiments were conducted using a CytoFLEX S cytometer (Beckman, USA). Isolation and analysis of mature immune cells and HSPC subsets. Peritoneal cells were collected by lavage with 10 mL DPBS (Corning, USA) using a 16-G needle. Cells were then incubated with red cell lysis buffer (BioLegend, USA) for 5 min and cultured in 6-well cell culture plates (Corning, USA) in complete media. After two hours, cells were washed once with DPBS (Corning, USA) and replenished with fresh complete media. Adherent cells were then collected for downstream analysis as peritoneal macrophages after one hour. For isolation and analysis of HSPC, cells were collected from the bone marrows or spleens and centrifuged at 300 x g, 5 min at 4°C, resuspended in red cell lysis buffer (BioLegend, USA) for 5 min and run through a 40 µm strainer. The cells were stained (Yamamoto et al., 2013) with a lineage-marker cocktail of biotinylated anti-CD4 (RM4-5), - CD8 (53-6.7), -B220/CD45RA (RA3-6B2), -TER-119 (TER-119), -Gr-1 (RB6-8C5), and - CD127 (IL-7Ra/A7R34) antibodies (from BioLegend, USA). These cells were then stained with anti-CD34 (RAM34, eBioscience, USA), anti-CD150 (TC15-12F12.2, BioLegend, USA), anti- CD48 (Invitrogen, USA), anti-Sca-1 (D7, Invitrogen, USA) anti-CD135 (A2F10, Invitrogen, USA) anti-c-Kit (2B8, Life Technologies, USA), anti-CD16/32 (93, BioLegend, USA), anti- CD41 (MWReg30, BioLegend, USA) and streptavidin-BV786 (BD Biosciences, USA) to detect biotinylated antibodies. Cells were then analyzed using a CytoFLEX S cytometer (Beckman, USA). Seahorse extracellular flux analysis. BMDM were plated at 60,000 cells/well into XFe24 cell culture microplates (Agilent, USA) and incubated overnight at 37°C and 5% CO2 while being treated with exosomes or PBS for 18 hours. The cells were then incubated with or without 100 ng/mL of LPS for 6 hours. Cells were then washed with Seahorse XF DMEM assay buffer (Agilent, USA) supplemented with 10 mM glucose (Agilent, USA), 1 mM pyruvate (Agilent, USA), and 2 mM glutamine (Agilent, USA) and incubated for 1 hour at 37°C without CO2. For measurements of oxidative phosphorylation, OCR and ECAR were measured using the mitochondrial stress test kit (Agilent, USA) in response to 1 µM Oligomycin, 2 µM Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and 0.5 µM Rotenone/Antimycin A (R/AA). For measurements of fatty acid oxidation, OCR and ECAR were measured in cells treated with 4 µM Etomoxir (Sigma Aldrich, USA) followed by 1 µM Oligomycin (Agilent, USA). For measurements of glycolytic activity, glycoPER was measured using the glycolytic rate assay (Agilent, USA) in response to 0.5 µM R/AA and 50 mM 2-deoxy-D-glucose (2-DG). The measurements were performed with the Seahorse XFe-24 Bioanalyzer (Agilent, USA). After OCR measurements, cells were incubated in Hoechst (1:1000) diluted in Live Cell Imaging Solution (Invitrogen, USA) and imaged under a Zeiss Observer microscope. Total cell counts were measured using ImageJ. Statistical Analysis. Statistical analysis was performed with GraphPad Prism v8, using the one-way or two-way analysis of variance (ANOVA) with post-tests, Holm-Sidak, as indicated in figure legends for multiple groups. *p < 0.05, **p < 0.01, ***p < 0.001 ****p < 0.0001. Normality test was performed using the Shapiro-Wilk test on GraphPad Prism v8, with p > 0.05 indicating normal distribution. The error bars represent the mean ± the standard error of the mean (SEM unless stated). The experiments were repeated at least twice or performed with independent samples. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMS We claim: 1. A method of reducing cardiometabolic inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

2. A method of treating or preventing atherosclerosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

3. A method of treating, preventing, or reducing cardiac failure in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

4. A method of treating or suppressing inflammation caused by hyperlipidemia in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

5. A method of increasing plasma IL-10 levels in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

6. A method of enhancing fatty acid oxidation and oxidative phosphorylation in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

7. A method of decreasing hematopoiesis in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

8. A method of decreasing myelopoiesis in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

9. A method of decreasing aortic leukocyte accumulation in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

10. A method of suppressing glycolysis and oxidative stress in immune cells, the method comprising administering to a subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

11. A method of decreasing cytokines in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

12. The method of any of the preceding claims, wherein the subject has been diagnosed with hyperlipidemia, type II diabetes, obesity-driven insulin resistance, or nonalcoholic fatty liver disease.

13. The method of any of the preceding claims, wherein the miR-146a agonist or mimic is miR-146a-5p, hsa-miR-146a-5p, or a fragment thereof.

14. The method of any of the preceding claims, wherein the miR-146a agonist or mimic is encoded by a nucleic acid.

15. The method of any of the preceding claims, wherein the miRNA-142 antagonist is an oligonucleotide that comprises a region that is complementary to miR-142.

16. The method of any of the proceeding claims, wherein the miR-146a agonist or mimic, the miR-142 antagonist is administered systemically.

17. The method of claim 16, wherein systemic administration is intravenous, intramuscular, or subcutaneous.

18. The method of any of the preceding claims, wherein the subject is identified in need of treatment before the administering step.

19. The method of any of the preceding claims, wherein the subject is a human.

20. The method of any of the preceding claims, wherein the miR-146a agonist or mimic, the miR-142 antagonist is located in a vector.

21. The method of claim 20, wherein the vector is a plasmid, cosmid, phagemid or a viral vector.

22. The method of claim 20, wherein the vector further comprises a lipid, lipid emulsion, liposome, nanoparticle or exosomes.

23. The method of any of the preceding claims, wherein the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof decrease one or more pro-inflammatory markers.

24. The method of claim 23, wherein the one or more pro-inflammatory markers are decreased in tissue macrophages or blood monocytes.

25. The method of claim 23 or 24, wherein the one or more pro-inflammatory markers are TNF ^, IL-6 IL-1 ^, MCP1, H2-Ab1, Cd86, or Cd80.

26. The method of any one of claims 1-23, wherein the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof increases one or more anti-inflammatory markers in one or more macrophages.

27. The method of claim 26, wherein one or more anti-inflammatory markers are IL-10, Arg1, Retnla, and Chil3.

28. The method of claim 10, wherein the immune cells are macrophages, blood monocytes, hematopoietic stem cells, or progenitor cells.

29. The method of any one of the preceding claims, wherein the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof increases mitochondrial activity in one or more macrophages, blood monocytes, hematopoietic stem cells, or progenitor cells.

30. A method of treating or ameliorating a symptom of a cardiometabolic disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

31. A method of treating or ameliorating a symptom of a chronic inflammatory disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

32. A method of ameliorating a symptom of atherosclerosis in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR- 146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

33. A method of enhancing oxidative phosphorylation in a cell of a subject in a subject, the method comprising administering to the subject a therapeutically effective amount of a miR-146a agonist or mimic, a miR-142 antagonist, or a combination thereof.

34. The method of claim 33, wherein the cell is an adipocyte or a macrophage in fat tissue.

35. The method of claim 33, wherein the cell is a hepatocyte or a macrophage in liver tissue.

36. The method of any one of claims 30-35, wherein the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof increase expression of one or more anti- inflammatory cytokines.

37. The method of claim 36, wherein the one or more anti-inflammatory cytokine is IL-10 or adiponectin.

38. The method of any one of claims 30-35, wherein the administration of the therapeutically effective amount of the miR-146a agonist or mimic, the miR-142 antagonist, or the combination thereof increase one or more M2-associated markers.

39. The method of claim 38, wherein the one or more M2-associated markers are Arg1, Retnla, or Chil3.