文献类型：期刊文献

英文题名：Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo

作者：Wang, Zhuang[1];Gu, Zhaoyan[1];Hou, Qing[2];Chen, Weijie[1];Mu, Di[1];Zhang, Yuanxing[1,3];Liu, Qin[1,3,4];Liu, Zhihong[2];Yang, Dahai[1,3]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Nanjing Univ, Jinling Hosp, Natl Clin Res Ctr Kidney Dis, Sch Med, Nanjing 210002, Peoples R China;[3]Shanghai Engn Res Ctr Maricultured Anim Vaccines, Shanghai 200237, Peoples R China;[4]Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao 266071, Peoples R China

年份：2020

卷号：204

期号：7

起止页码：1929

外文期刊名：JOURNAL OF IMMUNOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000521730100021)】；

基金：This work was supported by the National Natural Science Foundation of China (31622059), the Young Elite Scientists Sponsorship Program by China Association for Science and Technology (2016QNRC001), and Fundamental Research Funds for the Central Universities (222201714022).

语种：英文

摘要：The bacteria LPS is one of the leading endotoxins responsible for sepsis; its sensing pathway-induced pyroptosis plays an important role in innate immunity. However, excessive pyroptosis might cause immunological diseases, even multiple organ failure and death by undefined mechanisms. Given that the development of acute kidney injury (AKI) in patients with sepsis causes significant morbidity and mortality, the mechanism of pyroptosis in regulating septic AKI remains unknown. In this study, we establish a zebrafish crispant in vivo analysis model and reveal that both caspy2 and gasdermin Eb (GSDMEb) contribute to lethal LPS-induced septic shock. Meanwhile, the in vitro analysis reveals that caspy2 activation can specifically cleave GSDMEb to release its N terminus to mediate pyroptosis, which functions as GSDMD in mammals. Interestingly, we establish an in vivo propidium iodide-staining method and reveal that the caspy2-GSDMEb signaling cascade is essential for enhancing renal tubular damage during lethal LPS-induced septic shock, whereas administration of the zebrafish-specific GSDMEb-derived peptide inhibitor Ac-FEID-CMK can attenuate mortality and septic AKI in vivo. Moreover, we confirm that either caspase-11 or GSDMD deficiency decreases both inflammatory cytokines and kidney dysfunction enzyme release and prolongs survival in a murine model of septic shock. Taken together, these findings demonstrate an evolutionary executor for pyroptosis in zebrafish and reveal that the pyroptosis of renal tubular cells is a major cause of septic AKI, and also provide an ideal in vivo screening model for potential antisepsis therapeutic strategies.