期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 97, 期 6, 页码 645-660出版社
WILEY
DOI: 10.1002/jnr.24385
关键词
gasdermin D; ischemia; reperfusion injury; membrane translocation; NLRP3; pyroptosis
资金
- Project of Jiangsu Provincial Medical Innovation Team [CXTDA2017003]
- Jiangsu Provincial Medical Youth Talent [QNRC2016728]
- Suzhou Key Medical Center [Szzx201501]
- National Natural Science Foundation of China [81771255]
- Scientific Department of Jiangsu Province [BE2017656]
- Suzhou Government [LCZX201601]
- National Key R&D Program of China [2018YFC1312600, 2018YFC1312601]
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-1 beta 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.
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