CXCR1/HIF-1α正反馈环在调控DC细胞炎症因子分泌及自身免疫疾病中的作用及机制

发病机制不明、缺乏根治方法是目前自身免疫疾病的困境。前人及我们的成果已证实树突状细胞（DCs）炎症因子分泌失控、并过度激活效应T细胞是导致自身免疫疾病的关键，然而DCs炎症因子分泌失控的调控机制仍不清楚。本项目前期发现CXCR1受体可调控DCs炎症因子分泌，而敲除CXCR1显著减轻小鼠自身免疫疾病症状，同时HIF-1α与CXCR1之间存在正反馈调节。据此我们提出CXCR1/HIF-1α正反馈环诱导了DCs炎症因子分泌失控、以及自身免疫疾病发生的假说，并从三方面研究：一、证实DCs中CXCR1/HIF-1α之间存在正反馈调节机制；二、在元代细胞及小鼠体内系统研究此正反馈环对DCs炎症因子分泌能力的调控作用；三、利用全身和条件敲除小鼠、结合疾病建模来揭示DCs中的正反馈环在调控自身免疫疾病中的功能。本研究的开展将揭示DCs炎症因子分泌及自身免疫疾病发生的机制，并为疾病的诊治提供新的线索。

The major difficulties of autoimmune diseases are that the pathogenesis is unknown and there is no cure at present. Previous studies including ours demonstrated that the uncontrolled secretion of inflammatory cytokines by dendritic cells (DCs) and thus leading to Th1 and Th17 cell over-activation plays critical roles in autoimmune diseases, but the molecular mechanisms regulating the inflammatory cytokines secretion in DCs are still unclear. Our preliminary results showed that CXCR1 can regulate the inflammatory cytokines secretion by DCs，knockout of CXCR1 leads to alleviated symptoms of EAE, and we also found there exists a positive feedback regulation between CXCR1 and HIF-1α. Based on these data, we hypothesized that the positive feedback regulation between CXCR1 and HIF-1α promotes the production of inflammatory cytokines by DCs and ultimately boosts autoimmune diseases. And we plan to investigate this question in three steps: Firstly, we will confirm the existence of the feedback loop between CXCR1 and HIF-1α in DCs; Then we will explore if this feedback loop is intensively involved in regulation of the inflammatory cytokines secretion in DCs using in vitro, semi-in vivo and in vivo experiments; Finally we will use knockout and conditional knockout mice to verify the critical role of this feedback loop in autoimmune disease pathogenesis. This study will reveal the original mechanism regulating inflammatory cytokines production in DCs and the pathogenesis of autoimmune diseases, thus further may provide new diagnostic markers and therapeutic targets for autoimmune diseases treatment.