ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation
Year: 2021
Type: article
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.
Source: Redox Biology
Institutions: Kumamoto University, Nagasaki University, Tohoku University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,450
Awards: Elucidation of the redox activation mechanism of enterohemorrhagic Escherichia coli toxin SubAB and the infection control, G3975601500, Molecular mechanisms of NLRP3 inflammasome activation via glutathione efflux, G4839127209, Elucidation of cellular stress regulation through phospho-signals linking in and out of mitochondria, Sulfur-mediated energy metabolism, sulfur respiration: Its discovery and physiological functions, Molecular mechanisms of glutathione transport-dependent regulation of NLRP3 inflammasome, Mechanisms of intracellular bacterial killing induced by reactive sulfur species, Remodeling of reactive sulfur metabolism by reactive oxygen species-producing enzyme, Nox: Discovery of reactive sulfur remodelase, Life science basis of short-lived reactive species originated from foods, G8265722111
OpenAlex ID: W3138042889