Role of non-canonical pyroptosis in sepsis and other inflammatory diseases.

As a form of new programmed cell death, pyroptosis is divided into a canonical pyroptosis pathway and a non-canonical pyroptosis pathway. In recent years, it is reported that non-canonical pyroptosis is closely related to inflammatory reactions, which directly affects the occurrence, development, and outcome of sepsis, inflammatory bowel disease, respiratory disease, nerve system inflammatory disease, and other inflammatory diseases. When the cells were infected with Gram-negative bacteria or lipopolysaccharide (LPS), it can induce the activation of cysteinyl aspartate specific proteinase(caspase)-4/5/11 and directly bind to the cells to cleave gasdermin D (GSDM-D) into the active amino-terminus of GSDM-D. The amino-terminus of GSDM-D with membrane punching activity migrates to the cell membrane, triggering the rupture of the cell membrane, and the cell contents discharge, leading to the occurrence of non-canonical pyroptosis. After activation of caspase-11, it also promotes the canonical pyroptosis, activates and releases interleukin-1β and interleukin-18, which aggravated inflammation. Caspase-4/5/11, GSDM-D, Toll-like receptor 4 and high mobility group protein B1 are the key molecules of the non-canonical pyroptosis. Exploring the mechanisms of non-canonical pyroptosis and the related research progresses in inflammatory diseases intensively is of great significance for clinical prevention and treatment of the relevant diseases.细胞焦亡是一种新的程序性细胞死亡方式，分为经典和非经典途径细胞焦亡。近年报道非经典途径与炎症反应密切相关，直接影响脓毒血症、炎症性肠病、呼吸系统疾病、神经系统炎症性疾病等炎症性疾病的发生、发展及转归。当革兰氏阴性菌或脂多糖感染细胞时，可诱导胱天蛋白酶caspase-4/5/11激活，并在细胞内直接结合、切割gasdermin D(GSDM-D)蛋白生成有活性的GSDM-D氨基末端，切割后具有膜打孔活性的GSDM-D氨基末端迁移到细胞膜引起胞膜破裂，胞内容物流出，导致非经典途径细胞焦亡发生；caspase-11被激活后，同时促进经典途径细胞焦亡的发生，活化并释放白细胞介素-1β和白细胞介素-18，加剧炎症反应。Caspase-4/5/11、GSDM-D、Toll样受体4及高速泳动族蛋白B1是非经典细胞焦亡途径的关键分子。深入探讨非经典途径细胞焦亡的发生机制及其在炎症性疾病中作用的最新研究进展，对临床预防、治疗相关疾病具有重要意义。.