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Targeting the Proinflammatory Activity of Integrin Mac-1 for Treatment of Atherosclerosis

靶向整合素 Mac-1 的促炎活性治疗动脉粥样硬化

基本信息

批准号：
10376780
负责人：
LI ZHANG
金额：
$ 46.82万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376780
关键词：
Adhesions Affect Amino Acids Anti-Inflammatory Agents Arteries Atherosclerosis Autoimmune Diseases Binding Blood Vessels Bone Marrow Bone Marrow Transplantation C3bi CRISPR/Cas technology Cardiovascular Diseases Cell Adhesion Cell Differentiation process Cells Cessation of life Complement Coupled Data Development Disease Effectiveness Exhibits Fibrin Foam Cells High Fat Diet Homologous Gene Human Hyperlipidemia ITGAM gene ITGB2 gene In Vitro Inflammation Inflammatory Inflammatory Response Integrins Knock-in Mouse Lesion Leukocytes Ligand Binding Link LoxP-flanked allele Lupus Macrophage-1 Antigen Mediating Modeling Modern Medicine Molecular Mouse Strains Mus Mutate Mutation Pattern Phagocytosis Phenotype Play Population Process Production Property Publishing Reporting Risk Role Scanning Severities Signal Pathway Signal Transduction Supporting Cell Tamoxifen Testing Therapeutic Therapeutic Agents Transplantation Variant atheroprotective base cost cytokine design effective intervention experimental study genome wide association study in vivo insight loss of function loss of function mutation macrophage monocyte mouse model mutant novel novel strategies novel therapeutic intervention prevent receptor response targeted agent targeted treatment therapeutically effective vascular inflammation

项目摘要

A major player in the development of inflammatory diseases, such as atherosclerosis, is vascular macrophages, which are primarily derived from infiltrating monocytes in an integrin-dependent process. Mac-1 (CD11b/CD18, αMβ2 or CR3), a major integrin expressed on macrophages, is generally considered as a proinflammatory receptor. Surprisingly, we find that Mac-1 deficiency on an LDLR-/- background exacerbates atherosclerosis, which contradicts published observations obtained using bone marrow transplantation approaches. To resolve this discrepancy, we performed reciprocal bone marrow transplantation experiments, and our new data agree with the published results. Unexpectedly, they implicate the existence of a subset of Mac-1+ resident cells with atheroprotective functions. Also contradicting the paradigm of Mac-1 being a proinflammatory receptor, we discovered that Mac-1 possesses a novel anti-inflammatory activity (J Exp Med 2007). In support of our original finding, genome-wide association studies have linked loss-of-function Mac-1 variants in human population to a greater risk of lupus, an autoimmune disease that correlates with accelerated atherosclerosis. Thus, Mac-1 appears to both promote and inhibit the development of inflammatory diseases; however, the molecular mechanism that confers Mac-1 with these diametrically opposing activities is unknown. In our preliminary studies, we screened several existing homolog-scanning Mac-1 mutants and identified a novel Mac-1 variant (D289A290→KH) that abolishes Mac-1’s proinflammatory activity without compromising its anti-inflammatory functions. Subsequently, we generated a knock-in mouse, Mac-1NA, using the CRISPR/Cas9 technology, in which the homologous residues (N289A290) of murine Mac-1 were mutated. Our preliminary study revealed that Mac-1-/- and Mac-1NA mice exhibit opposite patterns of inflammatory responses in vitro and in vivo. Based on these exciting preliminary data, we hypothesize that Mac-1 expressed on a subset of aortic resident cells plays an atheroprotective role by suppressing vascular inflammation. To test our hypothesis, we generated a GFP-coupled Mac-1flox mouse, which was subsequently crossed with the tamoxifen-inducible CX3CR1-CreERT2 mouse. Using this novel CX3CR1-CreERT2;Mac-1flox strain, we successfully tagged resident macrophages but not monocytes with GFP and simultaneously deleted their Mac-1 expression. We propose to use this novel mouse strain to identify the atheroprotective subset of Mac-1-expressing resident cells. We will also establish molecular mechanisms underlying the differential ability of Mac-1-/- and Mac-1NA to regulate macrophage proliferation, intracellular signaling, and foam cell differentiation during the development of atherosclerosis. Finally, we will investigate novel strategies to selectively target Mac-1’s proinflammatory functions and test their effectiveness to reduce atherosclerosis. Completion of this project will provide new insights into the mechanism by which Mac-1 confers macrophages with pro- or anti-inflammatory properties. It can also assist us in the design of Mac-1-targeting agents to prevent and treat inflammatory diseases.

炎症性疾病（如动脉粥样硬化）发展的主要参与者是血管