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: 7896076
• 负责人: Huaizhu Wu
• 金额: $ 35.62万
• 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/7896076
• 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; Figs - dietary; 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）：肥胖增加了糖尿病和动脉粥样硬化心血管疾病（CVD）的风险。但是，基本机制仍然知之甚少。目前，众所周知，肥胖与通过脂肪组织（AT）和肝脏对细胞因子/趋化因子的分泌增加和分泌的慢性炎症相关，并且随肝脏产生富含甘油三酸酯的富甘油蛋白（TGRL）（TGRLS）的增加以及脂肪酸的水平增加（FAS，尤其是饱和FAS）。当前的数据表明，这些变化激活了血液和AT中的白细胞。血单核细胞激活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，并加速了AT的炎症。白细胞的积累和AT激活对于肥胖症的不良代谢和致病作用的发展可能至关重要。 CD11C是一种B2整合蛋白，主要在单核细胞/巨噬细胞和树突状细胞（DC）上表达，它是单核细胞/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FA的高脂饮食诱导的胰岛素抵抗的肥胖症会在血单核细胞和巨噬细胞上上调CD11c； （2）CD11C通过结合血管细胞粘附分子1（VCAM-1）来促进发炎内皮细胞（EC）的单核细胞粘附和迁移； （3）肥胖小鼠中CD11C的缺乏会减少动脉粥样硬化并在炎症时减少。因此，我们假设肥胖与CD11C表达增加的单核细胞激活有关，并且CD11C与包括CVD和糖尿病在内的肥胖相关疾病机械上有联系。提出了三个特定的目的来检验我们的假设：目标1。检查肥胖小鼠和人类中的血液单核细胞激活，包括CD11C表达。及其根据体重减轻和饮食中的二十碳烯酸（EPA）和二十二碳六烯酸（DHA）调节； AIM 2。确定CD11C在动脉粥样硬化发展以及单核细胞粘附和募集中的作用，通过使用高胆固醇血症的肥胖模型以及体外流量粘附测定和体内产生或不具有CD11C的血液单细胞的体外传递，通过使用肥胖的动物模型来促进动脉粥样硬化病变；和目标3。检查CD11c在炎症中的作用，包括巨噬细胞和T细胞的积累和激活； HF饮食诱导的肥胖症小鼠的代谢异常。这种方法将有助于我们更好地了解肥胖连接的炎症的机制，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。考虑到慢性炎症在与肥胖相关的CVD和代谢疾病中所表现出的作用，这种方法具有重大感兴趣，并且有可能为肥胖连接疾病提供新颖的预防和治疗靶标。 公共卫生相关性：肥胖与炎症有关，这有助于动脉粥样硬化和糖尿病的发展。我们的项目将研究CD11C（一种粘性的蛋白质对白细胞）在炎症中的作用，包括其对动脉粥样硬化的发展和与肥胖相关的糖尿病的贡献。这项研究有可能为与肥胖有关的动脉粥样硬化和糖尿病提供新的预防和治疗靶标。