Gasdermin D inhibition ameliorates neutrophil mediated brain damage in acute ischemic stroke.
Gasdermin D inhibition ameliorates neutrophil mediated brain damage in acute ischemic stroke.
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DOI：
10.1038/s41420-023-01349-6
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发表时间：
2023-02-08
影响因子：
7
通讯作者：
Song, Bo
中科院分区：
文献类型：
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作者：
Hu, Ruiyao;Liang, Jing;Ding, Lan;Zhang, Wan;Wang, Yuying;Zhang, Yige;Zhang, Ding;Pei, Lulu;Liu, Xinjing;Xia, Zongping;Xu, Yuming;Song, Bo
Acute ischemic stroke (AIS) induces high level of neutrophils, which correlates inversely with patient survival. Pyroptosis induced by gasdermin D (GSDMD) has been shown to have an important role in the pathophysiology of several inflammatory disorders. The role of GSDMD in the high level of neutrophils after AIS is unknown. Using a middle cerebral artery occlusion (MCAO) mouse model, we identified activation of pyroptosis signal, including expression of caspase-1/11, GSDMD, and interleukin-1β/18 (IL-1β/18), in the brain and spleen at early ischemic injury. Knockout of GSDMD in mice reduced infarct size, improved neurological function, and increased survival after MCAO. GSDMD deficiency decreased the overall degree of inflammation and the proportion of neutrophils in the brain after MCAO. Quantitative studies of neutrophils at several time intervals and organs demonstrated that early inflammatory leucocyte production and supplement (1 day after MCAO) was GSDMD-dependent. A series of bone marrow transplantation experiments, neutrophil depletion experiments, and RNA sequencing results demonstrated that neutrophil specific GSDMD is essential for the production and supply of neutrophil in bone marrow to blood. Moreover, pharmacological suppression of GSDMD decreased pathological abnormalities, infarct volume, and ameliorated neurological function. These results provided a new viewpoint on the immunological modulation of neutrophils after MCAO and suggest that suppression of GSDMD may relieve the neuroinflammatory load, thereby providing a potential treatment strategy for stroke. The absence of GSDMD reduces the high level of neutrophils in the brain, the production of neutrophils in bone marrow, and the supply of blood and spleen, while simultaneously the neutrophil-specific GSDMD signal deficiency restrains leukocytosis to improve the pathological outcome of AIS.
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DOI：
10.1038/s41573-021-00154-z
发表时间：
2021-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Liu X;Xia S;Zhang Z;Wu H;Lieberman J
通讯作者：
Lieberman J
影响因子：
64.8
作者：
通讯作者：
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影响因子：
56.9
作者：
HUANG, ZH;HUANG, PL;MOSKOWITZ, MA
通讯作者：
MOSKOWITZ, MA
影响因子：
16.6
作者：
Karmakar, Mausita;Minns, Martin;Pearlman, Eric
通讯作者：
Pearlman, Eric
缺血和再灌注 - 从翻译机构。
影响因子：
82.9
作者：
通讯作者：
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