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.

抽象的 脂肪组织免疫细胞的丰度和表型的变化是脂肪组织免疫细胞的主要决定因素 体重过度增加期间的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）挑战期间早期发生，并且与亲 MHCII 激活的 CD4+ 脂肪驻留 T 细胞 (ART) 的炎症变化表明脂肪细胞 肥胖引起的炎症的煽动者。为测试而创建的脂肪细胞特异性 MHCII 无效 (aMHCII-/-) 小鼠 这一假设 1) 与野生型相比，内脏脂肪组织 (VAT) 炎症明显减少 (WT) 同窝仔鼠在受到 HFD 挑战时，尽管体重和体脂百分比变化相同，2) VAT 调节性 T 细胞 (Treg) 明显增多，但其他外周部位则没有； 3）对胰岛素更敏感 具有更好的葡萄糖稳态，4) 当在易发生动脉粥样硬化的 LDLR-/- 背景中培育时， 减轻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。 Tregs 是一种 瘦小鼠中 CD4+ ART 群体的主要组成部分，它们抑制炎症以维持 VAT 代谢正常，但在 HFD 挑战期间急剧下降。然而，增值税 Tregs 被保留 在 HFD 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-/- 突变提供了一个独特的机会来特异性改变脂肪炎症， 独立于肥胖、血脂异常和外周T细胞的变化来研究其对肥胖的影响- 诱发并发症，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。具体目标将解决：1) A) 的影响 aMHCII 缺陷和 B) 内脏脂肪组织 (VAT) 特异性 Treg 耗竭（通过具有缺陷 VAT 的细胞） Treg 稳态或 IL-33 受体阻断抗体可抑制 IL-33 诱导的 VAT Treg 增殖） 关于饮食引起的动脉粥样硬化； 2) A) 组成型、脂肪细胞特异性 MHCII 过度表达是否促进 脂肪炎症增强动脉粥样硬化，B) IL-33 的施用可减轻动脉粥样硬化 通过增值税 Treg 依赖机制； 3）免疫细胞组成和分子的变化 使用主动脉 T 细胞流分析，观察有或没有 aMHCII 突变的小鼠主动脉病变的表型， 斑块巨噬细胞的激光捕获显微切割，以及巨噬细胞从 VAT 运输到的研究 主动脉。这项研究的结果使用脂肪细胞 MHCII 敲入/敲除模型和几种新颖的 专门改变 VAT（但不是外周血管）的方法，Tregs 将决定脂肪的贡献 组织炎症和 VAT Tregs 与肥胖相关动脉粥样硬化的发病机制有关。这 机制洞察为开发更好的基于免疫的治疗策略奠定了基础 肥胖背景下的CVD。

项目成果

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

脂肪细胞、先天免疫和肥胖：小型回顾。

• 发表时间: 2021
• 作者: Blaszczak, Alecia M;Jalilvand, Anahita;Hsueh, Willa A
• 通讯作者: Hsueh, Willa A

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

杰克逊心脏研究中黑人成人肥胖与糖尿病的关联。

• 发表时间: 2021-09-21
• 影响因子: 5.4
• 作者: Joseph, Joshua J;Kluwe, Bjorn;Echouffo;Zhao, Songzhu;Brock, Guy;Kline, David;Odei, James B;Kalyani, Rita R;Bradley, David P;Hsueh, Willa A;Sims, Mario;Golden, Sherita H
• 通讯作者: Golden, Sherita H

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

人类肥胖时脂肪细胞 DIO2 表达增加，但与全身胰岛素敏感性无关。

• 发表时间: 2018
• 作者: Bradley, David;Liu, Joey;Blaszczak, Alecia;Wright, Valerie;Jalilvand, Anahita;Needleman, Bradley;Noria, Sabrena;Renton, David;Hsueh, Willa
• 通讯作者: Hsueh, Willa

Human Visceral Adipose Tissue Macrophages Are Not Adequately Defined by Standard Methods of Characterization.

标准表征方法尚未充分定义人类内脏脂肪组织巨噬细胞。

• 发表时间: 2019
• 作者: Blaszczak, Alecia M;Jalilvand, Anahita;Liu, Joey;Wright, Valerie P;Suzo, Andrew;Needleman, Bradley;Noria, Sabrena;Lafuse, William;Hsueh, Willa A;Bradley, David
• 通讯作者: Bradley, David

Obesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance.

致肥记忆维持脂肪组织炎症和胰岛素抵抗。

• 发表时间: 2020
• 作者: Blaszczak, Alecia M;Bernier, Matt;Wright, Valerie P;Gebhardt, Gina;Anandani, Kajol;Liu, Joey;Jalilvand, Anahita;Bergin, Stephen;Wysocki, Vicki;Somogyi, Arpad;Bradley, David;Hsueh, Willa A
• 通讯作者: Hsueh, Willa A