Wang Kankai, Sun Zhezhe, Ru Junnan, Wang Simin, Huang Lijie, Ruan Linhui, Lin Xiao, Jin Kunlin, Zhuge Qichuan, Yang Su
Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Neurol. 2020 Nov 23;11:577927. doi: 10.3389/fneur.2020.577927. eCollection 2020.
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 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 and . In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke.
缺血/再灌注（I/R）损伤是全球范围内导致死亡和长期残疾的重要原因。最近的证据表明，一种新型细胞死亡形式——焦亡，在缺血性中风后导致炎症诱导的神经元死亡和神经功能损害。Gasdermin D（GSDMD）是新发现的细胞焦亡关键分子，但其生物学功能以及在缺血性中风中的精确作用仍不清楚。本研究调查了I/R后小鼠中GSDMD的切割活性、焦亡细胞的定位以及全身神经炎症。在脑I/R损伤急性期，梗死灶周围细胞焦亡水平显著升高。GSDMD缺失可减小梗死体积，并改善针对脑I/R损伤的神经功能。此外，我们证实I/R损伤主要在小胶质细胞中诱导细胞焦亡。敲低GSDMD可有效抑制小胶质细胞分泌成熟的IL-1β和IL-18，但不影响caspase-1/11的表达。总之，阻断GSDMD表达可能是缺血性中风的一种潜在治疗策略。
