可溶性白介素-17受体D(IL-17RD)通过促进TNF-α信号通路促发类风湿关节炎的机制研究

肿瘤坏死因子-α(TNF-α)在慢性炎症和自身免疫相关疾病中发挥重要作用，包括类风湿关节炎、狼疮性肾炎和自身免疫性糖尿病等。现有研究表明，TNF-α通过其受体介导的信号通路参与免疫反应的调节，但对其中的分子机制了解甚少。我们的前期研究发现，TNF-α通过促进巨噬细胞中TACE酶介导的白介素-17受体D(IL-17RD)胞外域脱落，产生的可溶性IL-17RD反过来又促进TNF-α介导的信号通路和炎症反应。因此，TNF-α诱导可溶性IL-17RD产生，是激活TNF-α信号通路并参与免疫调节的重要机制。在本项目中我们将进一步阐明TNF-α促进IL-17RD胞外域脱落分子机理，揭示可溶性IL-17RD在类风湿关节炎中的免疫调节作用机制，深入认识生物活性物质可溶性IL-17RD在炎症和自身免疫中的生物学功能，并进一步探索其在类风湿关节炎诊疗应用中的潜在价值。

Tumor necrosis factor-α (TNF-α) plays a crucial role in chronic inflammation and autoimmune diseases including rheumatoid arthritis, lupus nephritis and autoimmune diabetes. It has been shown that TNF-α is involved in the regulation of immune responses through its receptor-mediated signaling pathways, but little is known about the molecular mechanisms involved. In our previous study, we found that IL-17RD shedding is induced by TACE, an enzyme for protein cleavage, and enhanced by TNF-α in macrophages. Soluble IL-17RD in turn significantly enhances TNF-α-induced signaling and pro-inflammatory response. Therefore, TNF-α-induced production of soluble IL-17RD is an important mechanism that activates TNF-α signaling pathway and participates in immune regulation. In this study, we will clarify the mechanism of TNF-α promoting IL-17RD extracellular domain shedding, elucidate the immunomodulatory mechanism of soluble IL-17RD in rheumatoid arthritis, understand the biological function of bioactive soluble IL-17RD in inflammation and autoimmunity, and further explore its potential value in the diagnosis and treatment of rheumatoid arthritis.