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Macrophages are the primary effector cells in IL-7-induced arthritis


Synovial macrophages are crucial in the development of joint inflammation and bone damage; however, the pathways that control macrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined that elevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highly responsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine macrophages. The local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480+iNOS+ cells rather than CD3+ T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ induction. Hence, in RAG−/− mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lack of IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in the unique F480+iNOS+IL-7R+CCL5+ subset, with no impact on the F480+Arginase+ cell or CD3+ T cell frequency. Consistent with the preclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealed that IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480+iNOS+IL-7R+CCL5+ cell function, which activates TH-1 cells to amplify myeloid IL-7R expression and disease severity.

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This work was supported in part by awards from the Department of Veteran’s Affairs MERIT Award (1I01BX002286), the National Institutes of Health (AR056099 and AR065778), the UCB Investigator Initiated Award, and the National Psoriasis Foundation (NPF).

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All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. S.S. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: S.K. and S.S. Acquisition of data: S.K., M.V.V., K.P., S.U., K.V., R.Z., and S.S. Analysis and interpretation of data: S.K., H.C., K.P., S.U., K.V., J.C., M.M., D.F., and S.S. Providing reagents and involved in the phase 4 study: H.C., A.C., S.V., S.A., A.M., and N.S.

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Correspondence to Shiva Shahrara.

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Kim, Sj., Chang, H.J., Volin, M.V. et al. Macrophages are the primary effector cells in IL-7-induced arthritis. Cell Mol Immunol 17, 728–740 (2020).

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