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Abstract：
TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Herein, we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NF-κB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.
摘要：
TNF是已知其参与生理学和病理学的有效细胞因子。在类风湿性关节炎（RA）中，持续的TNF信号导致滑膜成纤维细胞（SF）的异常激活，常驻细胞主要参与受影响的滑膜的炎症和破坏性反应。然而,控制SF致病激活的分子开关仍然不明确。Cyld是去泛素化（DUB）机制的主要组成部分，调节细胞因子诱导的存活/炎症和程序性坏死的信号反应，生长因子和微生物产品。在这里，我们遵循功能遗传学方法来了解Cyld如何影响SFs中的关节炎TNF信号传导。我们证明，在自发性和诱导性RA模型中，SF-CyldDUB缺乏恶化关节炎表型由于趋化因子的水平增加，突变SF产生的粘附受体和骨降解酶。机械上,Cyld通过限制Tak1介导的信号传导来限制TNF诱导的SF过度激活，and,因此,导致监督的NF-κB和JNK活性。然而,Cyld并不严格参与TNF诱导的SF死亡的调节。我们的结果将SF-Cyld确定为TNF介导的关节炎的调节剂，并为支持SF反应的信号景观提供了信息。
