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.
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Acknowledgements
This work was financially supported by National Institute of Health HL134910 (to BCB and CY), HL140958 (to BCB), HL154318 (to CY), Department of Defense DM190884 (to BCB), New York State Department of Health C34726GG (to BCB and CGH), and University of Rochester Environmental Health Sciences Center P30 ES001247 (to BCB).
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CGH, MS, CY, BCB designed research; CGH, CLC, CZ, MS performed research; BCB contributed new reagents/ analytic tools; CGH, CZ analyzed data; CGH, CY, BCB wrote the paper.
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All of the experiments were approved by the University Committee on Animal Use For Research (UCAR) at the University of Rochester and followed National Institutes of Health guidelines for experimental procedures on mice. Human blood samples from healthy donors were collected and processed at the University of Rochester Medical Center following Institutional Review Board approval.
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Hsu, C.G., Chávez, C.L., Zhang, C. et al. The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis. Cell Death Differ 29, 1790–1803 (2022). https://doi.org/10.1038/s41418-022-00966-5
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DOI: https://doi.org/10.1038/s41418-022-00966-5
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