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

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 ATPinduced 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 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. and the final effector downstream of caspase-1 activation. Active caspases cleave GSDMD to generate an N-terminal cleavage product (GSDMD-NT) that forms transmembrane pores to enable IL-1β release and to drive pyroptosis (10-12). The importance of IL-1β as a disease mediator was confirmed by the CANTOS trial in which an IL-1β neutralizing antibody led to a lower rate of recurrent cardiovascular events in patients with previous myocardial infarction (13).Recent data suggest that endogenous lipids or their oxidation products can activate or inhibit the assembly of inflammasomes (5, 14). Among reactive aldehydes derived from lipid peroxidation, 4-hydroxynonenal (HNE) is the most abundant endproduct. The concentration of HNE in human serum is 0.05-0.15 μM under physiological conditions (15). However, HNE levels may reach 3-6 μM in tissues under oxidative stress (16,17). Because of its high solubility in aqueous fluids, the reactive HNE formed in membranes can diffuse into the cytoplasm. HNE is detoxified by conjugation to glutathione by glutathione S-transferase (18,19). However, some HNE molecules escape this mechanism and react with the side chains of cysteine, histidine and lysine residues in proteins (20)(21)(22). HNE thus has emerged as an important second messenger signaling molecule (18,19). For example, low concentrations of HNE produce beneficial effects, including the stimulation of endogenous antioxidant defense mechanisms and the inhibition of inflammation (19,(23)(24)(25)(26). Currently, two mechanisms are proposed for HNE-mediated regulation of inflammation. 1) HNE facilitates antioxidant expression by activating Nrf2 signaling, via disrupting Keap1−Nrf2 association and preventing Nrf 2 degradation (24,25,27). Nrf2 stimulates antioxidant expression and increases the resistance to cytotoxic reactive oxygen species (ROS), ther...

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Serum 4-hydroxynonenal associates with the recurrence of patients with primary cerebral infarction

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Elsholtzia bodinieri Vaniot Ameliorated Acute Lung Injury by NQO1, BCL2 and PTGS2 In Silico and In Vitro Analyses

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