Differential regulation of autoimmune arthritis by monocyte subsets

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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 of 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.