Role of beta2 integrins in macrophage retention and egress during inflammation

β2 整合素在炎症期间巨噬细胞保留和流出中的作用

• 批准号: 8821750
• 负责人: Valentin P Yakubenko
• 金额: $ 7.93万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2015-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821750
• 关键词: Adhesions; Adipose tissue; Adoptive Transfer; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood Circulation; CD18 Antigens; Cell Adhesion; Cell Line; Cell model; Cell surface; Cell-Cell Adhesion; Cells; Chronic; Data; Development; Diabetes Mellitus; Diet; Disease; Disease Progression; Dyes; Extracellular Matrix; Extracellular Matrix Proteins; Fluorescent Dyes; Foam Cells; GKLF protein; Goals; Health; ITGAM gene; ITGB2 gene; Immigration; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integrins; Label; Lead; Leukocytes; Ligand Binding; Ligands; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic syndrome; Methods; Migration Assay; Mission; Modeling; Mus; Mutate; National Heart, Lung, and Blood Institute; Obesity; Peptides; Peripheral; Peritoneal Macrophages; Pharmaceutical Preparations; Phenotype; Property; Regulation; Research; Resolution; Role; Site; Surface; Testing; Tissues; Up-Regulation; Work; atherogenesis; cell motility; density; design; in vivo; innovation; insight; macrophage; migration; monocyte; nanoparticle; novel; novel strategies; overexpression; prevent; receptor; receptor binding; trafficking

DESCRIPTION (provided by applicant): Recent studies demonstrate the importance of chronic low-grade inflammation for the development of many devastating diseases such as atherosclerosis, obesity and diabetes. The critical, yet still unclear, step of chronic inflammatio is macrophage accumulation in the inflamed peripheral tissue. The overall goal of this proposal is to test the contribution of b2 integrins to the retention and egress of macrophages within the site of inflammation, specifically during atherogenesis and obesity-induced diabetes. The objective of this work is to evaluate how different surface densities of related integrins ¿M¿2 and ¿D¿2, that have similar ligand binding properties, but an opposite effect on the development of inflammation, regulate the accumulation of macrophages in inflamed tissue. The central hypothesis is that the opposing contributions of integrins ¿M¿2 and ¿D¿2 to chronic inflammation depend on the different levels of expression of these integrins on the inflammatory macrophages. While a moderate density of ¿M¿2 supports macrophage egress from inflamed tissue, a high density of ¿D¿2 promotes macrophage retention within the site of inflammation. Guided by strong preliminary data, this hypothesis will be tested by pursuing three Specific Aims: 1. To evaluate the correlation between the contribution of ¿M¿2 and ¿D¿2 to metabolic syndrome and the level of b2 integrins expression at the sites of inflammation. 2. To identify the role of ¿M¿2 and ¿D¿2 in migration of M1 and M2 macrophages in vitro and macrophage trafficking in vivo during obesity-induced diabetes and atherogenesis. 3. To evaluate the effect of short ¿D segment on ¿D¿2-mediated migration in vitro and macrophage retention in adipose tissue and atherosclerotic lesions in vivo. Under the first aim, the role of ¿M- and ¿D-deficiency on the development of metabolic syndrome will be examined. This data will be supported by the analysis of ¿M and ¿D expression at the site of inflammation and the mechanism of its regulation on M1- and M2-activated macrophages. Under aim two, the migration of ¿D-/- and ¿M-/- macrophages will be evaluated using in vitro and in vivo approaches. Under aim three, the potential mechanism of inhibition of ¿D-mediated retention of macrophages will be studied using in vitro adhesion and migration assays and in vivo trafficking of adoptively transferred monocytes. The significance of these studies resides in providing new insights on the development of chronic inflammation focusing on the mechanism of macrophage retention, instead of studying macrophage migration to the inflammatory site. This proposal is innovative because the importance of integrin density on the cell surface for the progression and resolution of chronic inflammation has not been previously suggested. Hence, the hypothesis of integrin-dependent retention of macrophages at the site of inflammation proposes a qualitatively new approach for the treatment of chronic inflammatory diseases. Thus, the blocking of integrin ¿D during atherogenesis or diabetes can prevent macrophage accumulation at the inflammatory site stimulating the resolution of chronic inflammation and thwarting the progression of the disease.

描述（由申请人提供）：最近的研究表明，慢性低度炎症对于动脉粥样硬化、肥胖和糖尿病等许多破坏性疾病的发展具有重要意义，慢性炎症的关键但仍不清楚的步骤是巨噬细胞在炎症中的积累。该提案的总体目标是测试 b2 整合素对炎症部位内巨噬细胞保留和流出的贡献，特别是在动脉粥样硬化和肥胖引起的糖尿病期间。这项工作是为了评估相关整合素的不同表面密度如何？米克2 和 ¿ D?? 2，具有相似的配体结合特性，但对炎症的发展具有相反的作用，调节炎症组织中巨噬细胞的积累，核心假设是整合素的相反作用。米克2 和 ¿ D?? 2 慢性炎症取决于这些整合素在炎症巨噬细胞上的不同表达水平，而 ¿米克2 支持巨噬细胞从发炎组织中排出，高密度 ¿ D?? 2 促进炎症部位内的巨噬细胞滞留 在强有力的初步数据的指导下，该假设将通过追求三个具体目标进行检验： 1. 评估 ¿ 的贡献之间的相关性。米克2 和 ¿ D?? 2 代谢综合征和炎症部位 b2 整合素表达水平 2. 确定 ¿ 的作用。米克2 和 ¿ D?? 2 肥胖引起的糖尿病和动脉粥样硬化期间 M1 和 M2 巨噬细胞的体外迁移和体内巨噬细胞的运输 3. 评估短期 ¿ D 段 ¿ D?? 2介导的体外迁移和巨噬细胞在脂肪组织和体内动脉粥样硬化病变中的滞留首先是作用¿ M- 和 ¿ D-缺乏对代谢综合征发展的影响将受到 ¿ 分析的支持。 M 和 ¿炎症部位的 D 表达及其对 M1 和 M2 激活的巨噬细胞的调节机制在目标二下，¿ D-/- 和 ¿在目标三下，将使用体外和体内方法评估 M-/- 巨噬细胞的潜在抑制机制。将使用体外粘附和迁移测定以及过继转移的单核细胞的体内运输来研究 D 介导的巨噬细胞保留。这些研究的意义在于提供关于巨噬细胞保留机制的慢性炎症发展的新见解。研究巨噬细胞向炎症部位迁移的研究是创新的，因为细胞表面整合素密度对于慢性炎症的进展和消退的重要性尚未被提出。炎症部位的巨噬细胞为治疗慢性炎症疾病提供了一种全新的方法，因此，阻断整合素 ¿在动脉粥样硬化或糖尿病期间，D可以防止巨噬细胞在炎症部位积聚，从而刺激慢性炎症的消退并阻止疾病的进展。