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

描述（由申请人提供）：肥胖增加糖尿病和动脉粥样硬化性心血管疾病（CVD）的风险。然而，对潜在的机制仍然知之甚少。目前已知肥胖症与慢性炎症相关-其特征在于脂肪组织（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）的产生增加和脂肪酸（FA，特别是饱和FA）水平增加相关。目前的数据表明，这些变化激活血液和AT中的白细胞。血液单核细胞活化可增加单核细胞粘附和迁移，这与动脉粥样硬化的发展有关，并加速AT的炎症反应。AT中白细胞的积聚和活化可能是肥胖不良代谢和致病作用发展的关键。CD 11 c是主要在单核细胞/巨噬细胞和树突细胞（DC）上表达的b2整联蛋白，其是单核细胞/巨噬细胞活化的标志物并参与单核细胞募集。我们的初步研究结果表明：（1）富含饱和脂肪酸的高脂饮食诱导的肥胖伴胰岛素抵抗可上调血单核细胞和AT巨噬细胞表面的CD 11 c，（2）CD 11 c通过与血管细胞粘附分子-1（VCAM-1）结合促进单核细胞在炎症内皮细胞上的粘附和迁移;（3）肥胖小鼠中CD 11 c的缺乏减少动脉粥样硬化和AT炎症。因此，我们假设肥胖与单核细胞活化和CD 11 c表达增加有关，并且CD 11 c与肥胖相关疾病（包括CVD和糖尿病）有机械联系。提出了三个具体目标来检验我们的假设：目标1。检查血液单核细胞活化，包括CD 11 c的表达，在肥胖小鼠和人类;和它的调制减肥和饮食二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）;目的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测定和体内过继转移含或不含CD 11 c的血液单核细胞，确定增加的CD 11 c在动脉粥样硬化的发展中以及在单核细胞粘附和募集到动脉粥样硬化病变中的作用;以及目的3。检查CD 11 c在AT炎症中的作用，包括巨噬细胞和T细胞的积累和活化;以及在HF饮食诱导的肥胖小鼠的代谢异常中的作用。这种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CD 11 c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CVD和代谢疾病中的作用，这种方法具有重要意义，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，炎症有助于动脉粥样硬化和糖尿病的发展。我们的项目将研究CD 11 c（一种白色血细胞上的“粘性”蛋白）在炎症中的作用，包括其对动脉粥样硬化和肥胖相关糖尿病发展的贡献。这项研究有可能为肥胖相关动脉粥样硬化和糖尿病提供新的预防和治疗靶点。

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.