依赖GSDMD分泌的代谢物EET负反馈调节巨噬细胞焦亡的机制研究

细胞焦亡是一种炎症小体介导的促炎型细胞裂解死亡方式，作为固有免疫系统的重要组成部分，参与到机体抵抗病原菌感染以及炎症性疾病发生发展过程中。之后GSDMD的发现重新定义了细胞焦亡的概念，作为执行分子的GSDMD被成熟形式的Caspase-1和Caspase-11切割后上膜形成孔道，从而介导IL-1β和IL18的释放。近来一些学者发现GSDMD还可以释放一类称为警报素的蛋白，包括Galectin1和Galectin3。然而对于GSDMD孔能否分泌代谢物国内外尚无研究。我们前期研究通过组学分析筛选出GSDMD在焦亡过程中分泌的代谢物11,12-EET，并且在体内外水平证实了11,12-EET可以抑制不同炎症小体引起的细胞焦亡。本课题拟在已有研究基础上，深入研究11,12-EET调控细胞焦亡和相关炎症性疾病的发生及其具体作用机制，进而为治疗靶点提供理论依据。

Pryoptosis is a pro-inflammatory cell lytic death mediated by inflammasomes. As an important part of innate immunity, pryoptosis plays key roles in the control of infections and progression of inflammatory diseases. The discovery of GSDMD redefined the concept of pryoptosis. After its cleavage, GSDMD could form β-barrel pore on the cytoplasm membrane, leading to the secretion of inflammatory cytokines, such as IL-1β and IL18. Latest studies demonstrated that GSDMD pore could also secret alarmins proteins, like the galectin family. However, there is no report whether this pore could secret small molecular metabolites. Based on unbiased metabolomics, we screened 11,12-EET as a GSDMD-pore releasing metabolite during pryoptosis. We further proved 11,12-EET could inhibit pan-inflammasome mediated pryoptosis. This research intends to uncover the mechanisms of how 11,12-EET moderate cell pryoptosis and inflammatory disorders, which could provide therapeutic insights in these diseases.