Interleukin 9-induced tissue repair mechanisms in chronic inflammatory arthritis

慢性类风湿关节炎的特征是持续的滑膜炎症和基于软骨损伤和骨侵蚀的进行性关节破坏。基质细胞在破骨细胞介导的关节破坏的致病过程中发挥积极作用。目前的概念表明，促炎性和抗炎性细胞因子活性之间的不平衡会引发成纤维细胞样滑膜细胞的有害肥大，从而促进炎症和破骨细胞介导的骨破坏。虽然一些促炎细胞因子如TNFalpha在激活滑膜成纤维细胞样细胞和破骨细胞方面的作用已被深入研究，但潜在的负调节这些细胞的细胞因子在很大程度上是未知的。我们之前已经表明，白细胞介素(IL)-9似乎是诱导关节炎炎症消退的关键介质。重组IL-9治疗可缓解慢性炎症，减少组织损伤和骨质流失。我们现在提供的初步证据表明，除了IL-9对调节性T细胞激活的影响之外，IL-9/ il - 9r信号传导对基质细胞具有重要的调节功能。该项目将研究IL-9在人类关节疾病中对成纤维细胞样滑膜细胞和破骨细胞的作用，并在小鼠关节炎模型中使用功能增益和功能丧失方法解决IL-9诱导的组织修复机制。

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.