Gαq调控TLR4/IL-6参与类风湿关节炎发病机制的研究

Rheumatoid arthritis (RA) is one of the most common seen autoimmune diseases. TLR/IL-6 signaling pathway is important in RA pathogenesis. Our previous studies have demonstrated that Gαq was involved in regulation of RA pathogenesis, but the underlying mechanism is still not very clear. Our studies found that expression level of Gαq and IL-6 was negatively related in RA patients. IL-6 production by Gnaq-/- dendritic cells was significantly higher than WT dendritic cells after LPS stimulation. These data suggest that Gαq may involved in TLR4/IL-6 signaling in RA patients. Our project aims to clarify the potential molecular mechanism of how Gαq was involved in TLR4/IL-6 signaling with help of Gnaq-/- mice, and further confirm the role of Gαq in TLR4/IL-6 signaling in RA patients. This project will be the first one to demonstrate the role of Gαq in TLR4 signaling regulation, which will help us to know the molecular mechanism of RA pathogenesis better, and provide us more new insights in RA treatment.

类风湿关节炎(RA)是最常见的自身免疫性疾病之一，Toll样受体4/白介素-6（TLR4/IL-6）通路在RA的发病中有重要作用。我们曾证明Gαq参与RA发病的调控，但具体机制尚不明确。本项目预实验结果发现，RA患者中Gαq与IL-6的表达呈负相关，并且Gαq基因敲除 (Gnaq-/-)小鼠树突状细胞在LPS刺激后 IL-6的表达水平显著高于野生型（WT）小鼠树突状细胞，提示Gαq可能参与TLR4/IL-6通路的调控进而参与RA发病的调控。本项目拟借助 Gnaq-/-小鼠，明确Gαq对TLR4/IL-6通路的调控作用及具体的分子机制，并于RA患者中进一步验证。本项目的完成将首次证明Gαq参与TLR4的信号传导调控，阐明RA患者中TLR4/IL-6通路异常的机制，深入认识RA发病中的关键环节，为 RA 治疗新靶点的选择提供理论依据。

Gαq是Gq蛋白的α亚基，由Gnaq编码产生。既往的研究已证实Gαq为免疫调控中的重要分子。Toll样受体4/白介素-6(TLR4/IL-6 )通路在自身免疫性疾病的发病中有重要作用。本课题主要于树突状细胞（DC）中研究Gαq对TLR4活化后产生IL-6等的调控作用，旨在进一步阐明Gαq参与免疫调控的机制。本研究成果共发表SCI论文4篇，已接收SCI论文2篇。取得的主要成果包括：1、于Gnaq-/-小鼠 DC 及WT小鼠DC中检测TLR4活化后IL-6的产生水平，证实Gαq对IL-6产生的负调控作用；同时，于人细胞系HESC中敲除Gαq后检测TLR4活化后IL-6的产生水平，进一步证实Gαq对IL-6产生的负调控作用。2、于Gnaq-/-小鼠DC及WT小鼠DC中检测Gαq对DC的吞噬、活化、功能的调控作用，提示Gαq负调控DC的吞噬功能、共刺激功能以及诱导T细胞向Th17分化的功能。3、于Gnaq-/-小鼠DC及WT小鼠DC中检测TLR4活化后下游信号分子的变化，提示Gαq对ERK磷酸化的影响。4、于类风湿关节炎患者中进一步证实Gαq对IL-6的负调控作用。5、于干燥综合征患者、银屑病中进一步确认 Gαq 的免疫调控作用。除此之外，我们还做了：6、评估脊柱关节病新的自身抗体anti-CD74在中国脊柱关节病患者中的应用价值。7、总结了结缔组织病相关免疫性血小板减少性紫癜的临床特征。通过以上研究，我们对DC功能及TLR4/IL-6通路的调控机制有了进一步的认识，深入理解了自身免疫性疾病的发病机制，为自身免疫性疾病新靶点的选择提供了理论依据。