IRAK-1调控NLRP3炎性体通路在狼疮肾炎进展中的作用机制

固有免疫异常与狼疮发病密切相关。我们前期发现NLRP3炎症体通路活化促进炎症细胞浸润及Th17/Tregs失衡，加速狼疮肾炎(LN)进展。最新研究提示IRAK-1介导固有免疫反应中NLRP3炎症体通路活化，但IRAK-1是否通过调控NLRP3参与LN发病尚不明确。本课题在预实验提示IRAK-1介导狼疮巨噬细胞NLRP3活化的基础上，应用IRAK-1抑制剂和siRNA基因沉默等方法干预两种自发狼疮小鼠模型(MRL/lpr和NZB/WF1小鼠)，探讨在狼疮中IRAK-1对NLRP3炎性体通路活化、Th17和Tregs分化及对LN的影响；并用IRAK-1敲除小鼠诱导狼疮模型进一步验证。同时，体外探讨IRAK-1对自身dsDNA诱导的巨噬细胞和树突状细胞NLRP3炎性体通路活化的调控机制，及其对Th17和Tregs分化的作用。本项目有助于明确IRAK-1在LN中的作用机制并探索LN治疗新靶点。

Inappropriate innate immune response is closely associated with the pathogenesis of SLE. We have shown that NLRP3 inflammasome activation accelerates lupus nephritis (LN) via promoting inflammatory infiltration and Th17/Tregs imbalance. Recent studies suggest that IRAK-1 mediates the activation of NLRP3 inflammasome in innate immune response. However, it remains unclear whether IRAK-1 is involved in the pathogenesis of LN by modulating NLRP3 inflammasome. Based on our preliminary experiments showing that IRAK-1 regulates NLRP3 activation in murine lupus macrophages, the present project aims to explore the roles of IRAK-1 in regulating NLRP3 inflammasome pathway and Th17/Tregs balance as well as its impact on LN development. IRAK-1 inhibitor or IRAK-1 gene silencing in vivo will be used to treat two murine models of SLE (MRL/lpr and NZB/WF1 mice). The therapeutic efficacy and its underlying mechanisms will be investigated. In addition, pristance-induced lupus model will be created in IRAK-1 knockout mice for further verification. In vitro, the self dsDNA-activated macrophages and dendritic cells will be utilized to study the effects of IRAK-1 on NLRP3 inflammasome activation and the differentiation of Th17 and Tregs. This project will help to determine the role of IRAK-1 in LN and search for novel targets for the treatment of LN.