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.

说明(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，人们对其潜在机制仍知之甚少。目前已知，肥胖与慢性炎症有关--其特征是脂肪组织(AT)和肝脏产生和分泌细胞因子/趋化因子的增加--以及肝脏富含甘油三酯的脂蛋白(TGRL)的产生增加和脂肪酸(FAs，特别是饱和FAs)水平的增加。目前的数据表明，这些变化激活了血液和AT中的白细胞。单核细胞活化可增加单核细胞的黏附和迁移，参与动脉粥样硬化的发生发展，加速炎症反应。白细胞在AT中的积聚和激活可能在肥胖的不良代谢和致病效应的发展中起关键作用。CD11c是一种b2整合素，主要表达在单核/巨噬细胞和树突状细胞(DC)上，是单核/巨噬细胞活化的标志，参与单核细胞募集。我们的初步数据显示：(1)富含饱和脂肪酸的高脂饮食诱导的肥胖伴胰岛素抵抗上调单核细胞和AT巨噬细胞上CD11c的表达；(2)CD11c通过结合血管细胞黏附分子-1(VCAM-1)促进单核细胞在炎症内皮细胞(ECs)上的黏附和迁移；(3)肥胖小鼠CD11c缺乏可减轻动脉粥样硬化，减轻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，CD11c与肥胖相关疾病(包括心血管疾病和糖尿病)存在机械联系。我们提出了三个特定的目标来验证我们的假设：目的1.检测肥胖小鼠和人类的血液单核细胞活化，包括CD11c的表达；以及体重减轻和饮食中二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)对其的调节；目的2.通过建立肥胖合并高胆固醇血症的动物模型，通过体外流动黏附试验和体内有或没有CD11c的血液单核细胞过继转移，确定CD11c在AT炎症包括巨噬细胞和T细胞聚集和激活中的作用；以及HF饮食诱导的肥胖小鼠的代谢异常。这一方法将有助于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性疾病中的作用，这种方法具有重要的意义，并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展。我们的项目将研究CD11c在炎症中的作用，包括它在动脉粥样硬化和肥胖相关糖尿病的发展中的作用。CD11c是白细胞上的一种“粘性”蛋白。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。