Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome

单核细胞激活和 CD11c 在肥胖相关代谢综合征中的作用

• 批准号: 8231447
• 负责人: Huaizhu Wu
• 金额: $ 33.92万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231447
• 关键词: Abbreviations; Adhesions; Adipocytes; Adipose tissue; Adoptive Transfer; Animal Model; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Blood; Blood Circulation; Blood Vessels; Body Weight; Body Weight decreased; Cardiovascular Diseases; Cells; Chronic; Data; Dendritic Cells; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Endothelial Cells; Fatty Acids; Fatty acid glycerol esters; Fluorescence; Functional disorder; Glucose Intolerance; Hepatic; Human; ITGAX gene; In Vitro; Infiltration; Inflammation; Insulin Resistance; Integrins; Lead; Leukocytes; Link; Lipoproteins; Liver; Macrophage Activation; Metabolic; Metabolic Diseases; Metabolic syndrome; Mononuclear; Mus; N-3 polyunsaturated fatty acid; Nonesterified Fatty Acids; Obese Mice; Obesity; Obesity associated cardiovascular disease; Obesity associated disease; Play; Polymerase Chain Reaction; Prevention; Preventive; Production; Proteins; RNase protection assay; Reverse Transcription; Role; Smooth Muscle Myocytes; T-Cell Receptor; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Time; Toll-Like Receptor 2; Toll-like receptors; Triglycerides; Vascular Cell Adhesion Molecule-1; atherogenesis; chemokine; cytokine; diabetes risk; hypercholesterolemia; in vivo; interest; leukocyte activation; lipoprotein triglyceride; macrophage; migration; monocyte; novel; novel strategies; obesity treatment; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Obesity increases risk for diabetes and atherosclerotic cardiovascular disease (CVD). However, the underlying mechanisms remain poorly understood. It is currently known that obesity is associated with chronic inflammation-characterized by increased production and secretion of cytokines/chemokines by adipose tissue (AT) and liver-and with increased hepatic production of triglyceride-rich lipoproteins (TGRLs) and increased levels of fatty acids (FAs, saturated FAs in particular). Current data suggest that these changes activate leukocytes in blood and AT. Blood monocyte activation can increase monocyte adhesion and migration, which is implicated in the development of atherosclerosis and accelerates inflammation in AT. Leukocyte accumulation and activation in AT may be critical to the development of adverse metabolic and pathogenic effects of obesity. CD11c is a b2 integrin primarily expressed on monocytes/macrophages and dendritic cells (DCs) that is a marker for monocyte/macrophage activation and participates in monocyte recruitment. Our preliminary data show that: (1) obesity with insulin resistance induced by high-fat (HF) diet rich in saturated FAs up-regulates CD11c on blood monocytes and AT macrophages; (2) CD11c contributes to monocyte adhesion and migration on inflamed endothelial cells (ECs) by binding vascular cell adhesion molecule-1 (VCAM-1); and (3) deficiency of CD11c in obese mice reduces atherosclerosis and decreases AT inflammation. Therefore, we hypothesize that obesity is associated with monocyte activation with increased CD11c expression, and that CD11c is mechanistically linked to obesity-related diseases including CVD and diabetes. Three specific aims are proposed to test our hypotheses: Aim 1. Examine blood monocyte activation, including CD11c expression, in obese mice and humans; and its modulation by weight loss and by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); Aim 2. Determine the role of increased CD11c in the development of atherosclerosis and in monocyte adhesion and recruitment into atherosclerotic lesions by using animal models of obesity with hypercholesterolemia, and by in vitro flow adhesion assay and in vivo adoptive transfer of blood monocytes with or without CD11c; and Aim 3. Examine the role of CD11c in AT inflammation including macrophage and T cell accumulation and activation; and in metabolic abnormalities in mice with HF diet-induced obesity. This approach will help us better understand the mechanisms of obesity- linked inflammation, specifically the role of CD11c in recruitment and activation of macrophages and T cells in atherosclerotic lesions and AT. Considering the demonstrated role of chronic inflammation in obesity-related CVD and metabolic disease, this approach is of significant interest and has the potential to provide novel preventive and therapeutic targets for obesity-linked diseases. PUBLIC HEALTH RELEVANCE: Obesity is associated with inflammation, which contributes to the development of atherosclerosis and diabetes. Our project will study the role of CD11c, a "sticky" protein on white blood cells, in inflammation, including its contribution to the development of atherosclerosis and diabetes associated with obesity. This study has the potential to provide novel preventive and therapeutic targets for obesity-related atherosclerosis and diabetes.

描述（由申请人提供）：肥胖会增加患糖尿病和动脉粥样硬化性心血管疾病（CVD）的风险。然而，其根本机制仍知之甚少。目前已知，肥胖与慢性炎症有关，其特征是脂肪组织（AT）和肝脏细胞因子/趋化因子的产生和分泌增加，并且与肝脏富含甘油三酯的脂蛋白（TGRL）产生增加和脂肪酸水平增加有关（FA，特别是饱和 FA）。目前的数据表明，这些变化会激活血液和 AT 中的白细胞。血液中单核细胞的活化可以增加单核细胞的粘附和迁移，这与动脉粥样硬化的发展有关并加速 AT 的炎症。 AT 中白细胞的积累和激活可能对于肥胖的不良代谢和致病作用的发展至关重要。 CD11c 是一种 b2 整合素，主要在单核细胞/巨噬细胞和树突状细胞 (DC) 上表达，是单核细胞/巨噬细胞激活的标志物并参与单核细胞募集。我们的初步数据表明：（1）富含饱和脂肪酸的高脂（HF）饮食引起的肥胖伴胰岛素抵抗上调血液单核细胞和AT巨噬细胞上的CD11c； (2) CD11c 通过结合血管细胞粘附分子-1 (VCAM-1) 促进单核细胞在发炎内皮细胞 (EC) 上的粘附和迁移； (3) 肥胖小鼠 CD11c 缺乏可减少动脉粥样硬化并减少 AT 炎症。因此，我们假设肥胖与单核细胞活化和 CD11c 表达增加有关，并且 CD11c 在机制上与肥胖相关疾病（包括 CVD 和糖尿病）有关。提出了三个具体目标来检验我们的假设： 目标 1. 检查肥胖小鼠和人类的血液单核细胞活化，包括 CD11c 表达；及其通过减肥和膳食二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 的调节；目标 2. 通过使用肥胖伴高胆固醇血症的动物模型，并通过体外流动粘附试验和血液单核细胞的体内过继转移，确定增加的 CD11c 在动脉粥样硬化发展以及单核细胞粘附和募集到动脉粥样硬化病变中的作用CD11c；目标 3. 检查 CD11c 在 AT 炎症（包括巨噬细胞和 T 细胞积聚和激活）中的作用；以及HF饮食引起的肥胖小鼠的代谢异常。这种方法将帮助我们更好地了解肥胖相关炎症的机制，特别是 CD11c 在动脉粥样硬化病变和 AT 中巨噬细胞和 T 细胞的募集和激活中的作用。考虑到慢性炎症在肥胖相关心血管疾病和代谢疾病中的作用，这种方法具有重大意义，并且有可能为肥胖相关疾病提供新的预防和治疗靶点。 公共卫生相关性：肥胖与炎症有关，炎症会导致动脉粥样硬化和糖尿病的发生。我们的项目将研究 CD11c（一种白细胞上的“粘性”蛋白）在炎症中的作用，包括其对动脉粥样硬化和与肥胖相关的糖尿病的发展的贡献。这项研究有可能为肥胖相关的动脉粥样硬化和糖尿病提供新的预防和治疗靶点。