Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.
Gasdermin E dictates inflammatory responses by controlling the mode of neutrophil death.
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Gasdermin E通过控制中性粒细胞死亡的模式来决定炎症反应。
DOI：
10.1038/s41467-023-44669-y
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发表时间：
2024-01-09
影响因子：
16.6
通讯作者：
Luo, Hongbo R.
中科院分区：
文献类型：
--
作者：
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.
裂解细胞死亡和凋亡细胞死亡都能清除生物体中衰老和受损的细胞。然而，它们分别引发了截然不同的促炎和抗炎反应。支配这两种死亡模式之间选择的确切细胞机制仍然不完全清楚。在这里，我们确定Gasdermin E(GSDME)是中性粒细胞裂解性嗜酸性死亡的主开关。衰老的中性粒细胞中GSDME的裂解和激活受到严密的调控，由蛋白酶-3和caspase-3介导，导致上睑下垂。GSDME缺乏并不改变中性粒细胞的总体存活率；相反，它特异性地阻止了嗜中性粒细胞的松弛，并使中性粒细胞的死亡向凋亡倾斜，从而减轻了因巨噬细胞吞噬凋亡的中性粒细胞而引起的炎症反应。在临床相关的酸吸入诱导的肺损伤模型中，中性粒细胞特异性的GSDME缺失可减轻肺部炎症，促进炎症消退，并减轻肺损伤。因此，通过控制中性粒细胞死亡的模式，GSDME决定了宿主的炎症结果，为感染性和炎症性疾病提供了潜在的治疗靶点。凋亡和裂解细胞死亡途径都用于清除受损细胞；然而，下游的炎症结果根据所选途径的不同而有很大不同。在这里，作者表明，在中性粒细胞中存在Gasdermin E基因缺失的小鼠中，这些细胞在衰老时经历的是凋亡而不是嗜酸性细胞死亡，从而导致反应性炎症反应的减弱。
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.
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影响因子：
12.4
作者：
de Vasconcelos NM;Van Opdenbosch N;Van Gorp H;Parthoens E;Lamkanfi M
通讯作者：
Lamkanfi M
影响因子：
4.8
作者：
Dong, Siwen;Shi, Yujin;Dong, Xiaojing;Xiao, Xia;Qi, Jianli;Ren, Lili;Xiang, Zichun;Zhou, Zhuo;Wang, Jianwei;Lei, Xiaobo
通讯作者：
Lei, Xiaobo
影响因子：
5.7
作者：
Akino, Kimishige;Toyota, Minoru;Tokino, Takashi
通讯作者：
Tokino, Takashi
影响因子：
15.9
作者：
FOLKESSON, HG;MATTHAY, MA;BROADDUS, VC
通讯作者：
BROADDUS, VC
影响因子：
15.9
作者：
ATHENS, JW;WINTROBE, MM;RAAB, SO
通讯作者：
RAAB, SO