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

J Neurosci Res. 2019 Jun;97(6):645-660. doi: 10.1002/jnr.24385. Epub 2019 Jan 2.

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.

Keywords: NLRP3; gasdermin D; ischemia/reperfusion injury; membrane translocation; pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / complications
  • Brain Ischemia / metabolism*
  • Caspases / metabolism
  • Inflammasomes / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Microglia / metabolism
  • Phosphate-Binding Proteins / metabolism*
  • Pyroptosis*
  • Rats, Sprague-Dawley
  • Reperfusion Injury / complications
  • Reperfusion Injury / metabolism*

Substances

  • Gsdmd protein, rat
  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Phosphate-Binding Proteins
  • Casp4 protein, rat
  • Caspases

Associated data

  • GENBANK/157824040