Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro.

Abstract:

:Even though ischemic stroke is among the leading causes of death worldwide, the pathogenic mechanisms underlying ischemia reperfusion (I/R) brain injury remain unclear. Gasdermin D (GSDMD), as an important factor of pyroptotic death execution downstream of caspase-11 (noncanonical inflammasome) and caspase-1 (canonical inflammasome), may be implicated in I/R injury. The current study aimed to investigate the role and possible underlying mechanisms of GSDMD in pyroptosis during I/R injury. Results indicated that the nucleotide-binding oligomerization domain-like receptors (NLR family) pyrin domain containing 3 (NLRP3) inflammasomes were assembled and activated after middle cerebral artery occlusion/reperfusion (MCAO/R), leading to increased levels of IL-1β and IL-18. Additionally, GSDMD levels were elevated, and its N-terminal fragment (GSDMD-N) was cleaved to induce pyroptosis after MCAO/R, which was partly dependent on caspase-1 activation and its Asp280 amino acid site. Furthermore, it was found that GSDMD-N could bind to membrane lipids and exhibit membrane-disrupting cytotoxicity, depending on its Glu15 and Leu156 amino acid sites. Nevertheless, the C-terminal fragment of gasdermin (GSDMD-C) exhibited an auto-inhibitory effect on GSDMD-N-induced pyroptosis via binding to GSDMD in the cytoplasm. Taken together, this information suggests that GSDMD may participate in caspase-1-mediated pyroptosis during I/R injury both in vivo and in vitro, which could be a potential therapeutic target to reduce brain I/R injury.

journal_name

J Neurosci Res

authors

Zhang D,Qian J,Zhang P,Li H,Shen H,Li X,Chen G

doi

10.1002/jnr.24385

subject

Has Abstract

pub_date

2019-06-01 00:00:00

pages

645-660

issue

6

eissn

0360-4012

issn

1097-4547

journal_volume

97

pub_type

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