Differential regulation of autoimmune arthritis by monocyte subsets

描述（由申请人提供）：类风湿性关节炎（RA）是一种影响1%人口的炎症性自身免疫性疾病。单核细胞在RA的发病机制中起着关键作用，因为它们产生原炎性细胞因子，诱导组织损伤活化。人们认为，阻断单核细胞向关节的募集对RA患者有益。然而，阻断CCR2（一种单核细胞运输的趋化因子受体）在临床和实验中都失败了。这表明单核细胞可能代表具有相反免疫特性的多个群体。两种单核细胞亚群（Ly6Clow和Ly6Chigh）已经在小鼠和人类中被鉴定出来。ly6high单核细胞表达CCR2，而Ly6Clow单核细胞不表达CCR2。我们已经证明，ccr2缺陷小鼠外周没有ly6high单核细胞，这些小鼠发展为加重的胶原诱导关节炎（CIA），这是RA的一种实验模型。我们进一步证明，胶原免疫的CCR2缺陷小鼠淋巴结和关节炎关节中的Th17细胞增加，其中也含有丰富的中性粒细胞和Ly6Clow单核细胞。基于这些发现，我们假设这两种单核细胞亚群在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ly6high单核细胞通过抑制Th17细胞分化和抑制疾病。我们将通过体外和体内结合的方法来研究这一假设，包括从GFP或RFP报告小鼠中分离单核细胞亚群，Th17细胞和调节性T细胞（Tregs）的新生分化，跨内皮迁移试验，骨髓祖细胞单核细胞的体外分化，以及急性和慢性自身免疫性关节炎的诱导。我们相信，确定单核细胞亚群促进或抑制组织炎症的不同功能将促进对自身免疫性疾病病理生理学的理解，有助于制定更好的免疫细胞操作策略。

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.