Differential regulation of autoimmune arthritis by monocyte subsets

单核细胞亚群对自身免疫性关节炎的差异调节

基本信息

批准号：
8708501
负责人：
Peng Liu
金额：
$ 32.63万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708501
关键词：
Acute Affect Antigens Arthritis Attenuated Autoimmune Diseases Autoimmune Process Autoimmune Responses Biological Assay Blood Vessels Bone Marrow CD4 Positive T Lymphocytes Cell Differentiation process Cells Chemotactic Factors Chronic Coculture Techniques Collagen Collagen Arthritis Disease Effector Cell Experimental Models Functional disorder Generations Human Immune Immune Tolerance Immunologics Immunosuppressive Agents In Vitro Inflammation Inflammatory Interleukin-1 Interleukin-6 Invaded Joints Label Measures Mediating Migration Assay Modeling Mus NR4A1 gene Paper Pathogenesis Patients Peripheral Phenotype Play Population Production Property Publishing Recovery Regulation Regulatory T-Lymphocyte Reporter Reporting Resistance Rheumatoid Arthritis Role Severities T-Lymphocyte TNF gene Therapeutic Tissues Wild Type Mouse Work autoimmune arthritis base bone cell motility chemokine receptor cytokine improved in vivo joint injury lymph nodes macrophage monocyte mouse model neutrophil prevent progenitor reconstitution response trafficking

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting 1% of the population. Monocytes play a critical role in the pathogenesis of RA because they produce proimflammatory cytokines to induce tissue damage up activation. It was thought that blocking monocyte recruitment to the joints would benefit to RA patients. However, blockade of CCR2, a chemokine receptor for monocyte trafficking, failed both clinically and experimentally. This suggests that monocytes may represent multiple populations with opposing immunologic properties. Two monocyte subsets (Ly6Clow and Ly6Chigh) have been identified in both mouse and human. Ly6Chigh monocytes express CCR2 whereas Ly6Clow monocytes do not. We have shown that CCR2-deficient mice do not have Ly6Chigh monocytes in the peripheral and these mice develop exacerbated collagen-induced arthritis (CIA), an experimental model of RA. We further show evidence that collagen-immunized CCR2- deficient mice have increased Th17 cells in both the lymph nodes and the arthritic joints, which also contain abundant neutrophils and Ly6Clow monocytes. Based on these findings, we hypothesize that the two monocyte subsets have different function in CIA: Ly6Clow monocytes promote disease by enhancing the recruitment of Th17 cells and neutrophils while Ly6Chigh monocytes suppress Th17 cell differentiation and inhibit disease. We will investigate this hypothesis by combined in vitro and in vivo approaches including isolating monocyte subsets from GFP- or RFP- reporter mice, de novo differentiations of Th17 cells and regulatory T cells (Tregs), transendothelial migration assays, in vitro differentiation o monocyte from bone marrow progenitors, and induction of acute and chronic autoimmune arthritis. We believe that defining differential functions of monocyte subsets to promote or inhibi tissue inflammation will advance understanding of pathophysiology of autoimmune diseases, contributing toward better strategies for immune cell manipulation.

描述（由申请人提供）：类风湿关节炎（RA）是一种影响人群1％的炎症自身免疫性疾病。单核细胞在RA的发病机理中起关键作用，因为它们产生催化性细胞因子以诱导组织损伤激活。据认为，将单核细胞招募到关节中会受益于RA患者。但是，单核细胞运输的趋化因子受体CCR2封锁在临床和实验上都失败了。这表明单核细胞可能代表具有相对免疫学特性的多个种群。在小鼠和人类中都发现了两个单核细胞亚集（Ly6clow和Ly6chigh）。 Ly6chigh单核细胞表达CCR2，而Ly6clow单核细胞则没有。我们已经表明，CCR2缺陷型小鼠在周围没有Ly6chigh单核细胞，并且这些小鼠会形成加剧的胶原蛋白诱导的关节炎（CIA），这是RA的实验模型。我们进一步显示了证据表明，胶原蛋白免疫的CCR2缺陷小鼠在淋巴结和关节炎关节中均增加了Th17细胞，它们也含有丰富的中性粒细胞和Ly6clow单核细胞。基于这些发现，我们假设两个单核细胞子集在CIA中具有不同的功能：Ly6clow单核细胞通过增强Th17细胞和中性粒细胞的募集来促进疾病，而Ly6chigh单核细胞抑制TH17细胞分化和抑制疾病。 We will investigate this hypothesis by combined in vitro and in vivo approaches including isolating monocyte subsets from GFP- or RFP- reporter mice, de novo differentiations of Th17 cells and regulatory T cells (Tregs), transendothelial migration assays, in vitro differentiation o monocyte from bone marrow progenitors, and induction of acute and chronic autoimmune arthritis.我们认为，定义单核细胞亚群的差异功能促进或抑制组织炎症将提高对自身免疫性疾病的病理生理学的理解，从而有助于更好地进行免疫细胞操纵的策略。