ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation

Tianli Zhang, Hiroyasu Tsutsuki, Waliul Islam, Katsuhiko Ono, Kohsuke Takeda, Takaaki Akaike, Tomohiro Sawa

Research output: Contribution to journalArticlepeer-review

Abstract

The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders.

Original languageEnglish
Article number101930
JournalRedox Biology
Volume41
DOIs
Publication statusPublished - 2021 May
Externally publishedYes

Keywords

  • ATP
  • GSH efflux
  • Glutathione
  • NLRP3 inflammasome
  • Reactive oxygen species
  • Redox regulation

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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