肾脏树突状细胞(DCs)和Th17/Treg失衡与狼疮肾炎(LN)发病密切相关，而NLRP3/ASC/Caspase-1通路(主要表达于DCs)下游的关键分子IL-1β是调控Th17/Treg平衡的重要因素，但该通路在LN中作用不明。在前期发现狼疮肾炎NLRP3表达上调且与疾病活动相关的基础上，本课题拟(1)探讨MRL/lpr鼠肾脏NLRP3/ASC/Caspase-1通路表达及Th17/Treg平衡(数量、比例、表型和功能)变化及体内应用该通路抑制剂对Th17/Treg平衡的影响和对LN的治疗作用；(2)分离肾脏DCs与脾初始CD4+T细胞共培养，探讨正负调控该通路对Th17/Treg平衡的影响；(3)利用NLRP3、ASC和Caspase-1基因敲除鼠诱导狼疮模型进一步阐明其机制；(4)探讨LN患者肾活检标本中该通路与临床资料的相关性。本课题有助于探索LN的发病机制和发现新治疗靶点。

Renal dendritic cells (rDCs) and Th17/Treg imbalance are closely associated with the pathogenesis of lupus nephritis (LN), and as the key downstream molecule of NLRP3/ASC/Caspase-1 pathway(primarily expressed on DCs), IL-1β is an important regulator of Th17/Treg balance. However, the role and mechanism of NLRP3/ASC/ Caspase-1 pathway in LN remains unclear. On the basis of our preliminary findings that NLRP3 expression was upregulated and correlated with disease activity in LN, this project intends to (1)To investigate the expression of NLRP3/ASC/Caspase-1 pathway-related molecules and the Th17/Treg balance(quantity, proportion, phenotype and function) in MRL/lpr murine kidney as well as the effects of inhibitors in vivo on the Th17/Treg balance and LN; (2)Through positive and negative regulation, the influence of this pathway on the Th17/Treg balance will be explored in the co-culture system of renal dendritic cells (rDCs) and splenic naive CD4+T cells; (3)The induced lupus model based on NLRP3, ASC and Caspase-1 knockout mice will be applied to further clarify the mechanism; (4)To investigate the correlation between this pathway and clinical data in in renal biopsies from LN patients. This project will help to explore the pathogenesis and find new therapeutic targets in LN.