Impact of the Adipose Tissue Microenvironment on Atherosclerosis

脂肪组织微环境对动脉粥样硬化的影响

基本信息

批准号：
10063545
负责人：
Willa A Hsueh
金额：
$ 51.09万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063545
关键词：
Address Adipocytes Adipose tissue Affect Antigen Presentation Antioxidants Aorta Apolipoprotein E Atherosclerosis Attenuated Blocking Antibodies Blood Vessels Body Weight Body fat Bone Marrow Bone Marrow Transplantation C57BL/6 Mouse CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cells Cholesterol Communication Coronary artery Data Development Diabetes Mellitus Diet Disease Dyslipidemias Fc Receptor Gene Expression Goals Guidelines Harvest High Fat Diet Histocompatibility Antigens Class II Homeostasis Hyperlipidemia Hypertension Immune Immunotherapeutic agent Immunotherapy Inflammation Inflammatory Ingestion Insulin Insulin Resistance Interferons Investigation Knock-in Knock-out Leptin Lesion Lipids Low Density Lipoprotein Receptor Mediating Meta-Analysis Metabolic Metabolic syndrome Metabolism Modality Modeling Mus Mutation Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Overweight Paper Pathogenesis Peripheral Phenotype Plasma Population Production Regulatory T-Lymphocyte Risk Risk Factors Signal Transduction Site T-Lymphocyte Testing Th1 Cells Thinness Transgenes Transplantation Triglycerides Visceral Weight Wild Type Mouse adaptive immunity base blood glucose regulation cardiovascular disorder risk combat endothelial dysfunction excessive weight gain improved insight insulin sensitivity knock-down laser capture microdissection macrophage middle age molecular phenotype novel novel strategies obese person overexpression preservation protein expression receptor systemic inflammatory response trafficking tumor-immune system interactions

项目摘要

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.

抽象的脂肪组织免疫细胞的丰度和表型的变化是体重增加期间的全身性炎症和胰岛素抵抗。 II类的脂肪细胞表达主要的组织相容性复合物（MHCII）发生在高脂饮食（HFD）挑战期间的早期，并且相似之处 MHCII激活的CD4+脂肪常驻T细胞（ART）的炎症变化，将脂肪细胞作为肥胖引起的炎症的煽动者。脂肪细胞特异性MHCII null（AMHCII - / - ）为测试而创建的小鼠该假设1）与野生型相比，内脏脂肪组织（VAT）的炎症大大少得多（wt）同窝室时，当受到HFD挑战时，尽管体重不同，并且体重％变化，2）显着的增值税调节T细胞（Tregs），但在其他外围部位不明显； 3）对胰岛素更敏感具有更好的葡萄糖稳态，4）当繁殖到容易发生ldlr的动脉粥样硬化时 - / - 背景减弱的加速动脉粥样硬化而不影响血浆胆固醇和甘油三酸酯水平。 Treg是一个瘦小鼠中CD4+ ART人群的主要组成部分，它们抑制炎症以维持正常的增值税代谢，但在HFD挑战期间大幅下降。但是，保留了增值税在HFD喂养的AMHCII - / - 小鼠中，这可能解释了这些改善的代谢和心血管表型老鼠。因此独立于肥胖，血脂异常和周围T细胞的变化，以研究其对肥胖症的影响诱发并发症，特别是动脉粥样硬化。我们假设脂肪炎症减少即使在肥胖存在下，也会减弱动脉粥样硬化。具体目标将解决：1）a）的影响 AMHCII缺乏症和b）内脏脂肪组织（VAT）特异性Treg耗竭（通过具有缺陷桶的细胞 Treg稳态或IL-33受体阻断抗体，该抗体抑制IL-33诱导的VAT Treg增殖）关于饮食引起的动脉粥样硬化； 2）a）构成型脂肪细胞特异性MHCII过表达是否促进脂肪炎症以增强动脉粥样硬化，b）施用IL-33会减轻动脉粥样硬化通过增值税依赖性机制； 3）免疫细胞组成和分子的变化使用主动脉的T细胞流量分析，有或没有AMHCII突变的小鼠的主动脉病变中的表型，激光捕获斑块巨噬细胞的显微解剖，并研究了从增值税到的巨噬细胞运输主动脉。使用脂肪细胞MHCII敲入/敲除模型和几种新颖的研究结果特雷格（Tregs）专门改变增值税（但不是外围）的方法组织炎症和大桶Tregs对肥胖相关的动脉粥样硬化的发病机理。这机械洞察力为开发更好的免疫治疗策略奠定了舞台 CVD在肥胖的环境中。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Association of Serum Aldosterone and Plasma Renin Activity With Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.

DOI：
10.1161/circulationaha.120.050896
发表时间：
2021-06-15
期刊：
Circulation
影响因子：
37.8
作者：
Joseph JJ;Pohlman NK;Zhao S;Kline D;Brock G;Echouffo-Tcheugui JB;Sims M;Effoe VS;Wu WC;Kalyani RR;Wand GS;Kluwe B;Hsueh WA;Abdalla M;Shimbo D;Golden SH
通讯作者：
Golden SH

Adipocytes, Innate Immunity and Obesity: A Mini-Review.

脂肪细胞、先天免疫和肥胖：小型回顾。

DOI：
10.3389/fimmu.2021.650768
发表时间：
2021
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Blaszczak AM;Jalilvand A;Hsueh WA
通讯作者：
Hsueh WA

Adipocyte DIO2 Expression Increases in Human Obesity but Is Not Related to Systemic Insulin Sensitivity.

DOI：
10.1155/2018/2464652
发表时间：
2018
期刊：
Journal of diabetes research
影响因子：
4.3
作者：
Bradley D;Liu J;Blaszczak A;Wright V;Jalilvand A;Needleman B;Noria S;Renton D;Hsueh W
通讯作者：
Hsueh W

Obesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance.