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

Frontiers in Neurology

Zhezhe Sun¹  Linhui Ruan²  Simin Wang²  Lijie Huang²  Qichuan Zhuge²  Junnan Ru²  Su Yang²  Xiao Lin²  Kankai Wang²  Kunlin Jin³ 

[1] Department of Cerebrovascular, The Affiliated Hospital of Medical School of Ningbo University, Ningbo, China;Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States;Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China;

关键词: ischemia/reperfusion injury;    pyroptosis;    neuroinflammation;    gasdermin D;    microglia;    neurological outcome;   

DOI  :  10.3389/fneur.2020.577927

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown