Interleukin 9-induced tissue repair mechanisms in chronic inflammatory arthritis

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Chronic Rheumatoid arthritis is characterized by perpetuating synovial inflammation and progressive joint destruction based on cartilage damage and bone erosion. Stromal cells play an active role in the pathogenic process of osteoclast-mediated joint destruction. Current concepts suggest that an imbalance between pro- and anti-inflammatory cytokine activities triggers deleterious hypertrophy of fibroblast-like synoviocytes facilitating inflammation and osteoclast-mediated bone destruction. Whereas several pro-inflammatory cytokines such as TNFalpha are intensively studied in their contribution to activate synovial fibroblast-like cells and osteoclasts, potential cytokines that negatively regulate those cells are largely unknown. We have previously shown that Interleukin (IL)-9 appears as key mediator inducing resolution of inflammation in arthritis. Treatment with recombinant IL-9 resolved chronic inflammation and reduced tissue damage and bone loss. We now provide preliminary evidence that IL-9/IL-9R-signaling induces important regulatory functions on stromal cells beyond the already described influence of IL-9 on the activation of regulatory T cells. The proposed project will investigate the role of IL-9 on fibroblast-like synoviocytes and osteoclasts in human joint disease and address IL-9 induced tissue repair mechanisms using gain- and loss-of-function approaches in murine arthritis models.