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Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia

Ischemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D...

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Autores principales: Wang, Kankai, Sun, Zhezhe, Ru, Junnan, Wang, Simin, Huang, Lijie, Ruan, Linhui, Lin, Xiao, Jin, Kunlin, Zhuge, Qichuan, Yang, Su
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719685/
https://www.ncbi.nlm.nih.gov/pubmed/33329317
http://dx.doi.org/10.3389/fneur.2020.577927
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author Wang, Kankai
Sun, Zhezhe
Ru, Junnan
Wang, Simin
Huang, Lijie
Ruan, Linhui
Lin, Xiao
Jin, Kunlin
Zhuge, Qichuan
Yang, Su
author_facet Wang, Kankai
Sun, Zhezhe
Ru, Junnan
Wang, Simin
Huang, Lijie
Ruan, Linhui
Lin, Xiao
Jin, Kunlin
Zhuge, Qichuan
Yang, Su
author_sort Wang, Kankai
collection PubMed
description Ischemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D (GSDMD) is a newly discovered key molecule of cell pyroptosis, but its biological function and precise role in ischemic stroke are still unclear. The present study investigates the cleavage activity of GSDMD, localization of pyroptotic cells, and global neuroinflammation in gsdmd(−/−) mice after I/R. The level of cell pyroptosis around the infarcted area was significantly increased in the acute phase of cerebral I/R injury. The ablation of GSDMD reduced the infraction volume and improved neurological function against cerebral I/R injury. Furthermore, we confirmed I/R injury induced cell pyroptosis mainly in microglia. Knockdown of GSDMD effectively inhibited the secretion of mature IL-1β and IL-18 from microglia cells but did not affect the expression of caspase-1/11 in vitro and in vivo. In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke.
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spelling pubmed-77196852020-12-15 Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia Wang, Kankai Sun, Zhezhe Ru, Junnan Wang, Simin Huang, Lijie Ruan, Linhui Lin, Xiao Jin, Kunlin Zhuge, Qichuan Yang, Su Front Neurol Neurology Ischemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D (GSDMD) is a newly discovered key molecule of cell pyroptosis, but its biological function and precise role in ischemic stroke are still unclear. The present study investigates the cleavage activity of GSDMD, localization of pyroptotic cells, and global neuroinflammation in gsdmd(−/−) mice after I/R. The level of cell pyroptosis around the infarcted area was significantly increased in the acute phase of cerebral I/R injury. The ablation of GSDMD reduced the infraction volume and improved neurological function against cerebral I/R injury. Furthermore, we confirmed I/R injury induced cell pyroptosis mainly in microglia. Knockdown of GSDMD effectively inhibited the secretion of mature IL-1β and IL-18 from microglia cells but did not affect the expression of caspase-1/11 in vitro and in vivo. In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke. Frontiers Media S.A. 2020-11-23 /pmc/articles/PMC7719685/ /pubmed/33329317 http://dx.doi.org/10.3389/fneur.2020.577927 Text en Copyright © 2020 Wang, Sun, Ru, Wang, Huang, Ruan, Lin, Jin, Zhuge and Yang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Wang, Kankai
Sun, Zhezhe
Ru, Junnan
Wang, Simin
Huang, Lijie
Ruan, Linhui
Lin, Xiao
Jin, Kunlin
Zhuge, Qichuan
Yang, Su
Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title_full Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title_fullStr Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title_full_unstemmed Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title_short Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia
title_sort ablation of gsdmd improves outcome of ischemic stroke through blocking canonical and non-canonical inflammasomes dependent pyroptosis in microglia
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719685/
https://www.ncbi.nlm.nih.gov/pubmed/33329317
http://dx.doi.org/10.3389/fneur.2020.577927
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