Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation

作者：Yubin Liang, Pingping Song, Wei Chen, Xuemin Xie, Rixin Luo, Jie-hua Su, Yunhui Zhu, Jiamin Xu, Rongrong Liu, Peizhi Zhu, Yusheng Zhang, Min Huang · 发表于：Frontiers in Cellular Neuroscience · 年份：2021 · DOI：10.3389/fncel.2020.540669 · 被引用次数：95 · 研究领域：Inflammasome and immune disorders、Trace Elements in Health、Connexins and lens biology

Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1β and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression leve...