Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death

• Published in: Nature communications Vol. 15; no. 1; p. 386
• Main Authors: Ma, Fengxia, Ghimire, Laxman, Ren, Qian, Fan, Yuping, Chen, Tong, Balasubramanian, Arumugam, Hsu, Alan, Liu, Fei, Yu, Hongbo, Xie, Xuemei, Xu, Rong, Luo, Hongbo R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/2; 13/31; 14/19; 14/34; 631/250/1932; 631/250/1933; 631/250/2504/223/1699; 692/699/249/2510; Apoptosis; Caspase-3; Cell activation; Cell death; Deletion; Humanities and Social Sciences; Inflammatory diseases; Injury prevention; Leukocytes (neutrophilic); Lungs; Macrophages; Mortality; multidisciplinary; Neutrophils; Proteinase; Proteinase 3; Pyroptosis; Science; Science (multidisciplinary); Senescence; Survival; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44669-y

Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases. Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.