RIP1 在细菌诱导的炎症小体活化过程中的作用及机制研究

The host innate immune system is the first protective line of defense against invading pathogens. Inflammasome, as one of important components of innate immune system, has received intensive studies in this decade. Inflammasome-mediated caspase-1 activation and the secretion of cytokine IL-1β as well as IL-18, not only contribute to immune defense against bacteria, virus and fungi infection, but also play an important role in the development of inflammation-related diseases, such as tumor, atherosclerosis and diabetes. However, in many cases, the exact mechanism underlying inflammasome activation and regulation still remains unclear. RIP1 is a key regulator of signaling pathways regarding cell survival and cell death. Recent studies suggest that RIP1 is also involved in inflammation. Our previous work has provided first clues that bacteria Yersinia pestis-induced inflammasome activation might depend on RIP1, with unclear mechanism. This project will investigate the role of RIP1 in inflammasome activation induced by bacteria and the underlying mechanism. In addition, we will further investigate the in vivo role of RIP1 in inflammasome activation and innate immune response against bacterial infection. The results will help us comprehensively understand RIP1, and provide insight into the search for new therapeutic targets to treat bacterial infectious diseases.

天然免疫系统是机体抵御病原微生物入侵的第一道防线，炎症小体是该系统的重要成员之一，其介导的caspase-1活化以及炎症细胞因子IL-1β和IL-18的释放在对抗细菌、病毒等病原体感染以及肿瘤、动脉粥样硬化及糖尿病等炎症相关疾病的发生过程中扮演了重要角色。但许多情况下炎症小体活化及调控的机理仍不清楚。RIP1是细胞存活及死亡相关信号通路中的关键调控蛋白，最近研究表明RIP1还参与了炎症反应的调节。我们前期工作发现鼠疫耶尔森氏菌诱导的炎症小体活化可能依赖RIP1，但相关机理尚待研究。本项目拟对RIP1在细菌诱导的炎症小体活化过程中的作用及机制进行进一步研究，并利用动物模型研究RIP1在小鼠体内对抗细菌感染以及调控炎症小体活化过程中发挥的作用。研究结果将为全面了解RIP1蛋白提供新的视角和方向，并有助于阐明细菌感染中炎症小体的活化机制，为寻找治疗细菌感染的新的潜在靶点提供信息和理论依据。

RIP1蛋白（受体相互作用蛋白1）是细胞存活及死亡相关信号通路中的关键调控蛋白，最近的研究以及我们前期工作均发现RIP1还参与了炎症反应尤其是炎症小体活化的调节。本项目基于前期工作，进一步探讨了RIP1蛋白调控炎症小体活化的作用及相关分子机制。我们的研究结果发现在用经典诱导剂毒胡萝卜素TG或者布雷非德菌素BFA刺激巨噬细胞所建立的内质网应激模型中，RIP1蛋白及其激酶活性为炎症小体活化所必需。我们进一步研究了其中的分子机制，发现细胞坏死的另一个关键分子RIP3并不参与其中，而线粒体分裂蛋白DRP1和ROS则在RIP1调控炎症小体活化过程中发挥了重要作用。在此研究体系中，我们同时观察到白皮杉醇通过抑制氧化应激以及炎症小体活化而缓解内质网应激诱导的肝损伤等生物学效应。本项目综合利用不同的实验技术和研究体系，在分子、细胞和动物整体水平上揭示了RIP1蛋白介导内质网应激诱导炎症小体活化的新生物学功能，为利用RIP1作为治疗内质网应激相关疾病的药物靶点提供了理论和实验依据。项目资助发表SCI论文3篇，待发表1篇，参加国际会议并做分会场报告一次。