Interleukin 9-induced tissue repair mechanisms in chronic inflammatory arthritis

白细胞介素9诱导的慢性炎症性关节炎组织修复机制

• 批准号: 423477573
• 负责人: Privatdozent Dr. Andreas Ramming
• 金额: --
• 依托单位: Medizinische Klinik 3 - Rheumatologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/423477573?language=en
• 关键词: Interleukin; induced; tissue; repair; mechanisms

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.

慢性类风湿性关节炎的特征是以软骨损伤和骨侵蚀为基础的持续性滑膜炎症和进行性关节破坏。基质细胞在破骨细胞介导的关节破坏的发病过程中起着积极的作用。目前的概念认为，促炎和抗炎细胞因子活性之间的失衡触发成纤维细胞样滑膜细胞的有害肥大，促进炎症和破骨细胞介导的骨破坏。虽然几种促炎细胞因子如肿瘤坏死因子α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，但对这些细胞的潜在负性调节因子在很大程度上是未知的。我们先前已经证明，白介素9似乎是诱导关节炎炎症消退的关键介质。重组IL-9治疗缓解了慢性炎症，减少了组织损伤和骨丢失。我们现在提供的初步证据表明，除了已描述的IL-9对调节性T细胞激活的影响外，IL-9/IL-9R信号对基质细胞具有重要的调节功能。这项拟议的项目将研究IL-9在人类关节疾病中成纤维样滑膜细胞和破骨细胞上的作用，并利用小鼠关节炎模型中获得和丧失功能的方法解决IL-9诱导的组织修复机制。