The role of β2 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: 9261523
• 负责人: Valentin P Yakubenko
• 金额: $ 29.88万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261523
• 关键词: Adhesions; Adipose tissue; Adoptive Transfer; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Blood Circulation; Cell Adhesion; Cell Line; Cell model; Cell surface; 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; 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; novel therapeutics; 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（由适用提供）：最近的研究表明，慢性低级感染对许多毁灭性疾病（如动脉粥样硬化，肥胖症和糖尿病）的发展的重要性。慢性炎症的关键但不清楚的步骤是巨噬细胞在发炎的周围组织中的积累。该提案的总体目的是测试B2整合素对感染部位内巨噬细胞的保留和出口的贡献，特别是在动脉粥样硬化和肥胖引起的糖尿病期间。这项工作的目的是评估相关整合蛋白的不同表面密度如何 d.2，具有相似的配体结合特性，但对发炎组织的发展有相反的影响，它调节了发炎组织中巨噬细胞的积累。中心假设是整联蛋白的相反贡献是M。2和d.2对慢性发炎的影响取决于这些整联蛋白对发炎巨噬细胞的不同表达水平。虽然现代的密度为M.2支持发炎组织中的巨噬细胞出口，但高密度为d.2，促进了炎症部位内的巨噬细胞保留率。在强大的初步数据的指导下，将通过追求三个特定目的来检验该假设：1。评估'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贡献之间的相关性。 2。确定``M。2和d.2在体外体内在体外和巨噬细胞在肥胖诱导的糖尿病和动脉粥样硬化过程中的体外体内迁移中的作用。 3。评估短片段对脂肪组织和体内动脉粥样硬化病变中d.2介导的迁移和巨噬细胞保留的影响。在第一个目的下，将研究“ M-和d-d缺乏障碍在代谢综合征发展中的作用。该数据将通过对炎症部位的M和d表达​​进行分析以及其对M1和M2激活巨噬细胞的调节机制的支持。在目标两个下，将使用体外和体内方法评估d - / - 和 - / - 和 - / - 和 - / - 巨噬细胞的迁移。在AIM第三，使用体外广告和移民测定法以及适当转移的单核细胞的体内运输抑制了D介导的D介导的d介导的保留介导的保留的潜在机制。这些研究的重要性在于提供有关核噬细胞保留机制的智种感染发展的新见解，而不是研究巨噬细胞迁移到炎症部位。该建议具有创新性，因为以前尚未提出整联蛋白密度在细胞表面进展和分辨率的重要性。因此，在炎症提案部位，整联蛋白依赖依赖性巨噬细胞保留的假设是一种质量上新的治疗慢性炎性疾病的方法。这，在动脉粥样硬化或糖尿病期间整联蛋白的阻塞可以防止巨噬细胞在炎症部位积累，从而刺激慢性感染的分辨率并挫败疾病的进展。