狼疮肾炎(LN)是由自身免疫引起的肾脏炎症。我们报道NLRP3炎性体通路活化促进Th17/Tregs失衡及炎症细胞浸润，加速LN进展。Necroptosis是新发现的细胞死亡形式。最新发现necroptosis通路分子RIP3可直接介导炎症反应。本课题在预实验提示LN中有RIP3活化及RIP3能活化巨噬细胞NLRP3的基础上，应用化学抑制剂和siRNA基因沉默等方法干预MRL/lpr和NZB/W F1自发狼疮小鼠模型，探讨RIP3对NLRP3炎性体通路活化作用及其对LN进展的影响；并用RIP3基因敲除的NZM2328自发狼疮小鼠进一步验证。进而分离小鼠巨噬细胞、树突状细胞和肾小球足细胞，并对NZM2328足细胞株RIP3基因进行敲除，研究RIP3如何介导这些细胞参与狼疮肾脏炎症反应。

Lupus nephritis(LN) is the inflammation of the kidney induced by autoimmunity. We had previously shown that the activation of NLRP3 inflammasome pathway accelerated the progression of LN via inducing Th17/Tregs dysregulation and promoting inflammatory infiltration. Necroptosis is a newly described form of cell death. Recent studies showed that RIP3 mediates inflammation in addition to its involvement in the necroptosis. Our preliminary study showed that RIP3 was activated in LN and RIP3 can activate NLRP3 inflammasome in macrophages. In this study, chemical inhibitor and gene silencing by siRNA will be used to treat MRL/lpr and NZB/W F1 lupus-prone mice in vivo in order to investigate the roles of RIP3 on the activation of NLRP3 inflammasome pathway and its impacts on the progression of LN. The results will be further confirmed by using RIP3 knockout NZM2328 lupus-prone mice. Moreover, macrophages, dendritic cells and glomerular podocytes will be isolated from lupus-prone mice and RIP3 will be knocked out in NZM2328 podocyte cell line to investigate how RIP3 in these cells participates in the inflammation of the kidneys in lupus.