Hydrogen sulfide attenuates oxidative stress-induced NLRP3 inflammasome activation via S-sulfhydrating c-Jun at Cys269 in macrophages.

Oxidative stress and inflammation are closely related to cardiovascular diseases. Although hydrogen sulfide (H2S) has been shown to have powerful anti-oxidative and anti-inflammatory properties, its role in macrophage inflammation was poorly understood. The aim of this study was to investigate the role of H2S in the regulation of macrophage NLRP3 inflammasome activation. We reported here that H2S attenuated hydrogen peroxide (H2O2)-induced NLRP3 inflammasome activation, which led to caspase-1 activation and IL-1β production in macrophages. Moreover, H2S exerted its protective effects by lowering the generation of mitochondrial reactive oxygen species (mtROS). Mechanistically, S-sulfhydration of c-Jun by H2S enhanced its transcriptional activity on SIRT3 and p62, which contributed to the decrease of mtROS production. S-sulfhydration sites are investigated by site directed mutagenesis. Findings showed that S-sulfhydrated c-Jun exerted its protective influences via a c-Jun Cys269-dependent manner. Moreover, the protective effects of H2S were absent in macrophage from SIRT3 knockout mice. In conclusion, these results demonstrate that H2S attenuates oxidative stress-induced mtROS production and NLRP3 inflammasome activation via S-sulfhydrating c-Jun at cysteine 269 in macrophages.