Glutathione peroxidase 8 negatively regulates caspase‐4/11 to protect against colitis

Human caspase‐4 and its mouse homolog caspase‐11 are receptors for cytoplasmic lipopolysaccharide. Activation of the caspase‐4/11‐dependent NLRP3 inflammasome is required for innate defense and endotoxic shock, but how caspase‐4/11 is modulated remains unclear. Here, we show that mice lacking the oxidative stress sensor glutathione peroxidase 8 (GPx8) are more susceptible to colitis and endotoxic shock, and exhibit reduced richness and diversity of the gut microbiome. C57BL/6 mice that underwent adoptive cell transfer of GPx8‐deficient macrophages displayed a similar phenotype of enhanced colitis, indicating a critical role of GPx8 in macrophages. GPx8 binds covalently to caspase‐4/11 via disulfide bonding between cysteine 79 of GPx8 and cysteine 118 of caspase‐4 and thus restrains caspase‐4/11 activation, while GPx8 deficiency leads to caspase‐4/11‐induced inflammation during colitis and septic shock. Inhibition of caspase‐4/11 activation with small molecules reduces the severity of colitis in GPx8‐deficient mice. Notably, colonic tissues from patients with ulcerative colitis display low levels of Gpx8 and high caspase‐4 expression. In conclusion, these results suggest that GPx8 protects against colitis by negatively regulating caspase‐4/11 activity.