Differential regulation of autoimmune arthritis by monocyte subsets

描述(申请人提供)：类风湿性关节炎(RA)是一种炎症性自身免疫性疾病，影响1%的人口。单核细胞在类风湿关节炎的发病机制中起着关键作用，因为它们产生前炎性细胞因子来诱导组织损伤上调激活。据认为，阻止单核细胞募集到关节将对RA患者有利。然而，阻断CCR2，一种单核细胞运输的趋化因子受体，在临床和实验上都失败了。这表明单核细胞可能代表具有相反免疫特性的多个群体。在小鼠和人中都发现了两个单核细胞亚群(Ly6Clow和Ly6Chigh)。Ly6鸡单核细胞表达CCR2，而Ly6Clow单核细胞不表达CCR2。我们发现CCR2基因缺陷的小鼠外周血中没有Ly6Chigh单核细胞，这些小鼠发展为加重的胶原诱导性关节炎(CIA)，这是类风湿关节炎的一个实验模型。我们进一步的证据表明，胶原免疫的CCR2缺陷小鼠增加了淋巴结和关节炎关节中的Th17细胞，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，我们推测这两个单核细胞亚群在CIA中具有不同的功能：Ly6Clow单核细胞通过促进Th17细胞和中性粒细胞的募集而促进疾病，而Ly6Chigh单核细胞抑制Th17细胞的分化和抑制疾病。我们将通过体外和体内相结合的方法来研究这一假说，包括分离GFP或RFP报告小鼠的单核细胞亚群、Th17细胞和调节性T细胞(Tregs)的从头分化、跨内皮细胞迁移试验、从骨髓前体细胞体外分化单核细胞，以及诱导急性和慢性自身免疫性关节炎。我们相信，明确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的病理生理学的理解，有助于制定更好的免疫细胞操作策略。 公共卫生相关性：该提案旨在研究单核细胞亚群调节自身免疫性炎症的机制。特别是，我们将识别单核细胞亚群，通过促进或抑制效应细胞的生成或募集，如Th17细胞和中性粒细胞，来差异地调节自身免疫性关节炎的表达。

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. PUBLIC HEALTH RELEVANCE: This proposal intends to study the mechanisms by which monocyte subsets regulate autoimmune inflammation. In particular, we will identify monocyte subsets that differentially regulate autoimmune arthritis expression by either promoting or suppressing the generation or recruitment of effector cells, such as Th17 cells and neutrophils.