Impact of the Adipose Tissue Microenvironment on Atherosclerosis

摘要 脂肪组织免疫细胞的丰度和表型的变化是 超重期间的全身炎症和胰岛素抵抗。脂肪细胞II类分子的表达 主要组织相容性复合体(MHCII)发生在高脂饮食(HFD)挑战的早期，Parallels PRO. MHCII激活的CD4+脂肪驻留T细胞(ARTS)炎症变化提示脂肪细胞AS 肥胖引发炎症的煽动者。脂肪细胞特异性MHCII缺失(aMHCII-/-)小鼠 这一假设1)发生的内脏脂肪组织(VAT)炎症比它们的野生型要少得多 (WT)当用HFD挑战产仔时，尽管体重和体脂百分比变化相同，2) 明显更多的增值税调节性T细胞(Treg)，但不在其他外周部位；3)对胰岛素更敏感 具有更好的葡萄糖动态平衡和4)当培养成易于动脉粥样硬化的LDLR-/-背景时， 在不影响血浆胆固醇和甘油三酯水平的情况下减轻加速的动脉粥样硬化。特雷格是一种 瘦小鼠体内CD4+抗逆转录病毒治疗的主要成分，在那里他们抑制炎症以维持 VAT代谢正常，但在HFD攻击期间显著下降。但是，增值税树仍被保留 在高脂饲料喂养的aMHCII-/-小鼠中，这可能解释了这些小鼠代谢和心血管表型的改善 老鼠。因此，aMHCII-/-突变为特异性改变脂肪炎症提供了独特的机会， 与肥胖、血脂异常和外周T细胞变化无关，以研究其对肥胖的影响- 引起的并发症，特别是动脉粥样硬化。我们假设减少脂肪炎症 即使在肥胖的情况下也能减轻动脉粥样硬化。具体目标将涉及：1)A)的影响 AMHCII缺乏和B)内脏脂肪组织(VAT)特异性Treg耗竭(通过VAT缺陷的细胞 Treg动态平衡或IL-33受体阻断抗体抑制IL-33诱导的VAT Treg增殖) 关于饮食诱导的动脉粥样硬化；2)A)结构性的、脂肪细胞特异性的MHCII过度表达是否促进 脂肪炎症可增强动脉粥样硬化，B)应用IL-33可减轻动脉粥样硬化 通过VAT Treg依赖机制；3)免疫细胞组成和分子的变化 应用主动脉T细胞流图分析aMHCII基因突变小鼠的主动脉病变表型 斑块巨噬细胞激光捕获显微解剖及增值税向巨噬细胞转运的研究 大动脉。利用脂肪细胞MHCII基因敲入/敲除模型和几个新的模型研究结果 具体改变增值税的方法，但不是外围的，Tregs将确定脂肪的贡献 组织炎症和VAT受体在肥胖相关动脉粥样硬化发病机制中的作用。这 机械论洞察力为开发更好的基于免疫的治疗策略奠定了基础 心血管疾病与肥胖的关系。

ABSTRACT Changes in the abundance and phenotypes of adipose tissue immune cells are a major determinant of systemic inflammation and insulin resistance during excess weight gain. Adipocyte expression of the class II major histocompatibility complex (MHCII) occurs early during high-fat diet (HFD) challenge and parallels pro- inflammatory changes in MHCII-activated CD4+ adipose resident T cells (ARTs) implicating the adipocyte as an instigator of obesity-induced inflammation. Adipocyte-specific MHCII null (aMHCII-/-) mice created to test this hypothesis 1) developed substantially less visceral adipose tissue (VAT) inflammation than their wild-type (WT) littermates when challenged with HFD, despite identical changes in body weight and %body fat, 2) had markedly more VAT regulatory T cells (Tregs), but not in other peripheral sites; 3) were more insulin sensitive with better glucose homeostasis and 4) when bred into an atherosclerosis prone LDLR-/- background, attenuated accelerated atherosclerosis without affecting plasma cholesterol and triglyceride levels. Tregs are a major component of the CD4+ ART population in lean mice, where they suppress inflammation to maintain normal VAT metabolism, but dramatically decrease during HFD-challenge. However, VAT Tregs are preserved in HFD-fed aMHCII-/- mice, which likely explains the improved metabolic and cardiovascular phenotype in these mice. The aMHCII-/- mutation, thus, provides a unique opportunity to specifically alter adipose inflammation, independent of obesity, dyslipidemia, and changes in peripheral T cells to investigate its impact on obesity- induced complications, particularly atherosclerosis. We hypothesize that decreased adipose inflammation attenuates atherosclerosis even in the presence of obesity. Specific Aims will address: 1) the effect of A) aMHCII-deficiency and B) visceral adipose tissue (VAT)-specific Treg depletion (via cells with defective VAT Treg homeostasis or an IL-33 receptor blocking antibody which inhibits IL-33-induced VAT Treg proliferation) on diet-induced atherosclerosis; 2) whether A) constitutive, adipocyte-specific MHCII overexpression promotes adipose inflammation to enhance atherosclerosis, and B) administration of IL-33 attenuates atherosclerosis through a VAT Treg-dependent mechanism; and 3) changes in the immune cell composition and molecular phenotypes in aortic lesions in mice with and without aMHCII mutations using T cell flow analyses of aorta, laser capture microdissection of plaque macrophages, and investigation of macrophage trafficking from VAT to aorta. The results of this investigation using adipocyte MHCII knock-in/knock-out models and several novel approaches to specifically alter VAT, but not peripheral, Tregs will determine the contributions of adipose tissue inflammation and VAT Tregs to the pathogenesis of obesity-associated atherosclerosis. This mechanistic insight sets the stage for development of better immune-based therapeutic strategies to combat CVD in the setting of obesity.