The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis View Full Text


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Article Info

DATE

2022-03-09

AUTHORS

Chia George Hsu, Camila Lage Chávez, Chongyang Zhang, Mark Sowden, Chen Yan, Bradford C. Berk

ABSTRACT

Pyroptosis is a form of cell death triggered by the innate immune system that has been implicated in the pathogenesis of sepsis and acute lung injury. At the cellular level, pyroptosis is characterized by cell swelling, membrane rupture, and release of inflammatory cytokines, such as IL-1β. However, the role of endogenous lipids in pyroptosis remains underappreciated. We discovered that 4-hydroxynonenal (HNE), a major endogenous product of lipid peroxidation, inhibited pyroptosis and inflammasome activation. HNE at physiological concentrations (3 µM) blocked nigericin and ATP-induced cell death, as well as secretion of IL-1β, by mouse primary macrophages and human peripheral blood mononuclear cells. Treatment with HNE, or an increase of endogenous HNE by inhibiting glutathione peroxidase 4, reduced inflammasome activation in mouse models of acute lung injury and sepsis. Mechanistically, HNE inhibited the NLRP3 inflammasome activation independently of Nrf2 and NF-κB signaling, and had no effect on the NLRC4 or AIM2 inflammasome. Furthermore, HNE directly bound to NLRP3 and inhibited its interaction with NEK7. Our findings identify HNE as a novel, endogenous inhibitor of the NLRP3 inflammasome. More... »

PAGES

1790-1803

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41418-022-00966-5

    DOI

    http://dx.doi.org/10.1038/s41418-022-00966-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1146148485

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35264781


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