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: 8672747
• 负责人: Valentin P Yakubenko
• 金额: $ 26.55万
• 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: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672747
• 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; 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; public health relevance; 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许多破坏性疾病（如动脉粥样硬化、肥胖和糖尿病）的发展具有重要意义。慢性炎症的关键步骤是巨噬细胞在发炎的外周组织中的积聚，但这一点尚不清楚。本提案的总体目标是测试b2整合素对炎症部位内巨噬细胞的滞留和排出的贡献，特别是在动脉粥样硬化形成和肥胖诱导的糖尿病期间。这项工作的目的是评估不同的表面密度的相关整合素<$M <$2和 D 2，具有相似的配体结合特性，但对炎症的发展具有相反的作用，调节炎症组织中巨噬细胞的积累。中心假设是整合素<$M <$2和<$D <$2对慢性炎症的相反贡献取决于这些整合素在炎性巨噬细胞上的不同表达水平。虽然中等密度的<$M <$2支持巨噬细胞从发炎组织中排出，但高密度的<$D <$2促进巨噬细胞保留在炎症部位内。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标来检验：1。评价<$M <$2和<$D <$2对代谢综合征的贡献与炎症部位b2整合素表达水平之间的相关性。2.确定下列人员的作用：米2、？D？2在体外M1和M2巨噬细胞的迁移和在体内肥胖诱导的糖尿病和动脉粥样硬化形成过程中的巨噬细胞运输中的作用。3.评估短<$D段对<$D <$2介导的体外迁移和体内脂肪组织和动脉粥样硬化病变中巨噬细胞滞留的影响。在第一个目标下，将检查<$M和<$D缺乏对代谢综合征发展的作用。该数据将通过分析炎症部位的<$M和<$D表达及其对M1和M2激活的巨噬细胞的调节机制来支持。在目标二下，将使用体外和体内方法评价<$D-/-和<$M-/-巨噬细胞的迁移。在目标三下，将使用体外粘附和迁移试验以及过继转移的单核细胞的体内运输来研究抑制D介导的巨噬细胞滞留的潜在机制。这些研究的意义在于为慢性炎症的发展提供新的见解，重点是巨噬细胞滞留的机制，而不是研究巨噬细胞迁移到炎症部位。该提议具有创新性，因为之前尚未提出细胞表面整合素密度对于慢性炎症进展和消退的重要性。因此，巨噬细胞在炎症部位的整合素依赖性滞留的假说提出了一种治疗慢性炎症性疾病的定性新方法。因此，在动脉粥样硬化形成或糖尿病期间阻断整合素D可以防止巨噬细胞在炎症部位的积聚，从而刺激慢性炎症的消退并阻止疾病的进展。