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Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.

ABSTRACT: MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated.To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1?Mac/ApoE-/-) mice and found that atherosclerosis was greater in MED1?Mac/ApoE-/- mice than in MED1fl/fl/ApoE-/- littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1?Mac/ApoE-/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1?Mac mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPAR? (peroxisome proliferator-activated receptor ?) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPAR? and MED1 increased the binding of PPAR? or MED1 to the PPAR response elements of M2 marker genes.Our data suggest that MED1 is required for the PPAR?-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPAR?-regulated transactivation.

SUBMITTER: Bai L

PROVIDER: S-EPMC5739054 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.

Bai Liang L Li Zhao Z Li Qianwei Q Guan Hua H Zhao Sihai S Liu Ruihan R Wang Rong R Zhang Jin J Jia Yuzhi Y Fan Jianglin J Wang Nanping N Reddy Janardan K JK Shyy John Y-J JY Liu Enqi E

Arteriosclerosis, thrombosis, and vascular biology 20170622 8

<h4>Objective</h4>MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated.<h4>Approach and results</h4>To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1<sup>ΔMac</sup>/ApoE<sup>-</sup><sup>/-</sup>) mice and found tha ...[more]

PMID: 28642237

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Project description:ObjectiveBy binding to its high-affinity receptor FcεR1, IgE activates mast cells, macrophages, and other inflammatory and vascular cells. Recent studies support an essential role of IgE in cardiometabolic diseases. Plasma IgE level is an independent predictor of human coronary heart disease. Yet, a direct role of IgE and its mechanisms in cardiometabolic diseases remain incompletely understood. Approach and Results: Using atherosclerosis prone Apoe-/- mice and IgE-deficient Ige-/- mice, we demonstrated that IgE deficiency reduced atherosclerosis lesion burden, lesion lipid deposition, smooth muscle cell and endothelial cell contents, chemokine MCP (monocyte chemoattractant protein)-1 expression and macrophage accumulation. IgE deficiency also reduced bodyweight gain and increased glucose and insulin sensitivities with significantly reduced plasma cholesterol, triglyceride, insulin, and inflammatory cytokines and chemokines, including IL (interleukin)-6, IFN (interferon)-γ, and MCP-1. From atherosclerotic lesions and peritoneal macrophages from Apoe-/-Ige-/- mice that consumed an atherogenic diet, we detected reduced expression of M1 macrophage markers (CD68, MCP-1, TNF [tumor necrosis factor]-α, IL-6, and iNOS [inducible nitric oxide synthase]) but increased expression of M2 macrophage markers (Arg [arginase]-1 and IL-10) and macrophage-sterol-responsive-network molecules (complement C3, lipoprotein lipase, LDLR [low-density lipoprotein receptor]-related protein 1, and TFR [transferrin]) that suppress macrophage foam cell formation. These IgE activities can be reproduced in bone marrow-derived macrophages from wild-type mice, but muted in cells from FcεR1-deficient mice, or blocked by anti-IgE antibody or complement C3 deficiency.ConclusionsIgE deficiency protects mice from diet-induced atherosclerosis, obesity, glucose tolerance, and insulin resistance by regulating macrophage polarization, macrophage-sterol-responsive-network gene expression, and foam cell formation.

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Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.

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Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization.

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