IgE Contributes to Atherosclerosis and Obesity by Affecting Macrophage Polarization, Macrophage Protein Network, and Foam Cell Formation
IgE Contributes to Atherosclerosis and Obesity by Affecting Macrophage Polarization, Macrophage Protein Network, and Foam Cell Formation
复制标题
IgE 通过影响巨噬细胞极化、巨噬细胞蛋白网络和泡沫细胞形成而导致动脉粥样硬化和肥胖
DOI：
10.1161/atvbaha.119.313744
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Guo Junli
中科院分区：
文献类型：
--
作者：
Zhang Xian;Li Jie;Luo Songyuan;Wang Minjie;Huang Qin;Deng Zhiyong;de Febbo Caroline;Daoui Aida;Liew Pei Xiong;Sukhova Galina K.;Metso Jari;Jauhiainen Matti;Shi Guo-Ping;Guo Junli
目的IgE通过与其高亲和受体FcεR1结合，激活肥大细胞、巨噬细胞及其他炎症和血管细胞。最近的研究支持IgE在心脏代谢疾病中的重要作用。血浆IgE水平是人类冠心病的独立预测因子。然而，IgE在心脏代谢疾病中的直接作用及其机制仍不完全清楚。方法与结果在动脉粥样硬化易发apoe - / -小鼠和IgE-缺陷小鼠中，我们发现IgE缺乏降低了动脉粥样硬化病变负荷、病变脂质沉积、平滑肌细胞和内皮细胞含量、趋化因子MCP（单核细胞趋化蛋白）-1的表达和巨噬细胞的积累。IgE缺乏还会减少体重增加，增加葡萄糖和胰岛素敏感性，显著降低血浆胆固醇、甘油三酯、胰岛素和炎症细胞因子和趋化因子，包括IL（白细胞介素）-6、IFN（干扰素）-γ和MCP-1。从食用致动脉粥样硬化饮食的apoe−/−Ige−/−小鼠的动脉粥样硬化病变和腹腔巨噬细胞中，我们检测到M1巨噬细胞标志物（CD68、MCP-1、TNF[肿瘤坏死因子]-α、IL-6和iNOS[诱导型一氧化氮合酶]）的表达降低，而M2巨噬细胞标志物（Arg[精氨酸酶]-1和IL-10）和巨噬细胞-甾醇反应网络分子（补体C3、脂蛋白脂肪酶、低密度脂蛋白受体]相关蛋白1）的表达增加。TFR[转铁蛋白])抑制巨噬细胞泡沫细胞的形成。这些IgE活性可以在野生型小鼠的骨髓源性巨噬细胞中重现，但在fc ε r1缺陷小鼠的细胞中减弱，或被抗IgE抗体或补体C3缺乏阻断。结论sige缺乏通过调节巨噬细胞极化、巨噬细胞-甾醇反应网络基因表达和泡沫细胞形成，保护小鼠饮食诱导的动脉粥样硬化、肥胖、糖耐量和胰岛素抵抗。
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 ResultsUsing atherosclerosis proneApoe−/−mice and IgE-deficientIge−/−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 fromApoe−/−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.