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

Fengxia Ma (), Laxman Ghimire, Qian Ren, Yuping Fan, Tong Chen, Arumugam Balasubramanian, Alan Hsu, Fei Liu, Hongbo Yu, Xuemei Xie, Rong Xu and Hongbo R. Luo ()
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Fengxia Ma: Chinese Academy of Medical Sciences & Peking Union Medical College
Laxman Ghimire: Boston Children’s Hospital
Qian Ren: Chinese Academy of Medical Sciences & Peking Union Medical College
Yuping Fan: Chinese Academy of Medical Sciences & Peking Union Medical College
Tong Chen: Chinese Academy of Medical Sciences & Peking Union Medical College
Arumugam Balasubramanian: Boston Children’s Hospital
Alan Hsu: Boston Children’s Hospital
Fei Liu: Boston Children’s Hospital
Hongbo Yu: VA Boston Healthcare System, Department of Pathology and Laboratory Medicine
Xuemei Xie: Boston Children’s Hospital
Rong Xu: Boston Children’s Hospital
Hongbo R. Luo: Boston Children’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44669-y

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