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  2. Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo

Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo

  • J Immunol. 2020 Apr 1;204(7):1929-1942. doi: 10.4049/jimmunol.1901456.
Zhuang Wang 1 Zhaoyan Gu 1 Qing Hou 2 Weijie Chen 1 Di Mu 1 Yuanxing Zhang 1 3 Qin Liu 1 3 4 Zhihong Liu 2 Dahai Yang 5 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
  • 2 National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
  • 3 Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China; and.
  • 4 Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China.
  • 5 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China; [email protected].
Abstract

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.

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