基于线粒体自噬调控NLRP3炎症小体活化探讨肠安Ⅱ号方治疗IBS-D低度炎症的作用机制

The important pathological basis of low-grade inflammation in diarrhea-predominant Irritable bowel syndrome is the release of pro-inflammatory cytokines after activation of intestinal mucosa innate immunity. As the important pattern recognition receptor, NLRP3 is the key sensor of microbial pathogens and self-danger signals. NLRP3 interacts with the adaptor protein ASC which further recruits pro-caspase-1 to form a large protein complex, called NLRP3 inflammasome. The activation of NLPR3 inflammasome results in the release of pro-inflammatory cytokines and inflammatory response. NLRP3 inflammasome can be invoked by mitochondrial ROS and inhibited by mitophagy, which can help us find a new breakthrough for the prevention of IBS-D. Previous research results showed that Chang’an Ⅱ Decoction could relieve low-grade inflammation, lower the expression of IL-1β and decrease oxidative stress. However, further research should be carried out to clarify the decoction’s effect via mitophagy. In order to illuminate the mechanism of Chang’an Ⅱ Decoction , IBS-D rats model and macrophage inflammation model in vitro will be established for detecting related protein of NLRP3 inflammasome and related index of mitophagy. The project will further clarify the pathogenesis of IBS-D and the important target of Chinese medicine compound , which will be beneficial for the prevention of IBS-D.

肠黏膜固有免疫系统激活后释放促炎细胞因子是IBS-D肠黏膜低度炎症的重要病理基础。 NLRP3作为固有免疫重要的模式识别受体，是外源性微生物及内源性危险信号的感受器，可招募ASC、Caspase-1装配成NLRP3炎症小体，活化后释放促炎细胞因子，诱导肠黏膜炎症反应。线粒体来源的活性氧是激活炎症小体的关键因子；而巨噬细胞可通过线粒体自噬抑制炎症小体活化，为IBS-D防治找到新的突破口。前期研究结果表明肠安Ⅱ号方可降低IBS-D肠黏膜低度炎症，下调IL-1β表达，减少机体氧化应激反应，但能否通过线粒体自噬发挥作用，有待进一步研究。本项目以IBS-D模型大鼠和体外巨噬细胞炎症模型为研究对象，通过检测炎症小体相关蛋白表达、线粒体自噬相关指标探讨肠安II号对IBS-D低度炎症的调控作用。本研究可进一步阐明IBS-D的病理机制及中药干预的重要靶标，对IBS-D防治意义重大。

肠黏膜固有免疫系统激活后释放促炎细胞因子是IBS-D肠黏膜低度炎症的重要病理基础。 NLRP3作为固有免疫重要的模式识别受体，是外源性微生物及内源性危险信号的感受器，可招募ASC、Caspase-1装配成NLRP3炎症小体，活化后释放促炎细胞因子，诱导肠黏膜炎症反应。线粒体来源的活性氧是激活炎症小体的关键因子；而巨噬细胞可通过线粒体自噬抑制炎症小体活化，为IBS-D防治找到新的突破口。本项目以IBS-D干预脾虚证病证结合大鼠和体外巨噬细胞炎症模型为研究对象，通过检测炎症小体相关蛋白表达、线粒体自噬相关指标探讨肠安II号对IBS-D低度炎症的调控作用。研究结果表明，肠安II号方一方面可下调 NLPR3、pro-IL-1β 和 pro-IL-18 蛋白表达阻断 NLRP3 炎症小体诱导装配，另一方面可通过调控线粒体自噬抑制 NLRP3 炎症小体激活，从而可多途径、多环节阐明肠安II号方调控 IBS-D 低度炎症的作用机制。本研究可进一步阐明IBS-D的病理机制及中药干预的重要靶标，对IBS-D防治意义重大。