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

• 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
• 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

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.

摘要 脂肪组织免疫细胞的丰度和表型的变化是一个主要的决定因素， 全身炎症和胰岛素抵抗。II类脂肪细胞表达 主要组织相容性复合体（MHCII）在高脂饮食（HFD）挑战期间早期出现，并与前 MHCII激活的CD 4+脂肪驻留T细胞（ARTs）的炎症变化暗示脂肪细胞是 肥胖引发炎症的罪魁祸首创建脂肪细胞特异性MHCII空（aMHCII-/-）小鼠以测试 这一假设1）与野生型相比， (WT)当用HFD激发时，尽管体重和%体脂的变化相同，但2） 显著增加VAT调节性T细胞（Tcells），但在其他外周部位没有; 3）胰岛素敏感性更高 具有更好的葡萄糖稳态和4）当繁殖到动脉粥样硬化倾向的LDLR-/-背景中时， 减弱加速的动脉粥样硬化而不影响血浆胆固醇和甘油三酯水平。Tumblr是一个 瘦小鼠中CD 4 + ART群体的主要组成部分，在那里它们抑制炎症， 正常的VAT代谢，但在HFD激发期间显著降低。然而，增值税税率被保留 在HFD喂养的aMHCII-/-小鼠中，这可能解释了这些小鼠中代谢和心血管表型的改善。 小鼠因此，aMHCII-/-突变提供了特异性改变脂肪炎症的独特机会， 独立于肥胖、血脂异常和外周T细胞的变化，以研究其对肥胖的影响- 引起并发症，特别是动脉粥样硬化。我们假设减少脂肪炎症 即使在肥胖症的情况下也能减弱动脉粥样硬化。具体目标将解决：1）A）的影响 aMHCII缺乏和B）内脏脂肪组织（VAT）特异性Treg耗竭（通过具有缺陷性VAT的细胞 Treg稳态或抑制IL-33诱导的VAT Treg增殖的IL-33受体阻断抗体） 2）A）组成性脂肪细胞特异性MHCII过表达是否促进 脂肪炎症以增强动脉粥样硬化，和B）施用IL-33减弱动脉粥样硬化 通过VAT Treg依赖性机制;和3）免疫细胞组成和分子水平的变化， 使用主动脉的T细胞流动分析在具有和不具有aMHCII突变的小鼠中的主动脉病变中的表型， 斑块巨噬细胞的激光捕获显微切割，以及巨噬细胞从VAT到 主动脉本研究使用脂肪细胞MHCII敲入/敲除模型和几种新的MHCII基因敲除模型， 特别是改变VAT的方法，但不是外围的，TdR将决定脂肪的贡献， 组织炎症和血管内皮生长因子对肥胖相关动脉粥样硬化发病机制的影响。这 机械的洞察力为开发更好的基于免疫的治疗策略奠定了基础， 心血管疾病在肥胖的背景下。

项目成果

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.

• DOI: 10.20900/immunometab20200023
• 发表时间: 2020-01-01
• 期刊: Immunometabolism
• 作者: Blaszczak, Alecia M;Bernier, Matt;Hsueh, Willa A
• 通讯作者: Hsueh, Willa A

Association of Adiposity With Incident Diabetes Among Black Adults in the Jackson Heart Study.

• DOI: 10.1161/jaha.120.020716
• 发表时间: 2021-09-21
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Joseph JJ;Kluwe B;Echouffo-Tcheugui JB;Zhao S;Brock G;Kline D;Odei JB;Kalyani RR;Bradley DP;Hsueh WA;Sims M;Golden SH
• 通讯作者: Golden SH