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.

中文翻译：

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谷胱甘肽过氧化物酶8负调节caspase-4 / 11以防止结肠炎。

人胱天蛋白酶4及其小鼠同源胱天蛋白酶11是细胞质脂多糖的受体。先天性防御和内毒素性休克需要激活caspase-4 / 11依赖性NLRP3炎性小体，但是尚不清楚caspase-4 / 11的调控方式。在这里，我们显示缺乏氧化应激传感器谷胱甘肽过氧化物酶8（GPx8）的小鼠更容易患结肠炎和内毒素性休克，并且肠道微生物组的丰富性和多样性降低。经历过GPx8缺陷型巨噬细胞过继性细胞转移的C57BL / 6小鼠表现出相似的增强结肠炎表型，表明GPx8在巨噬细胞中起关键作用。GPx8通过GPx8的半胱氨酸79和caspase-4的半胱氨酸118之间的二硫键与caspase-4 / 11共价结合，从而抑制caspase-4 / 11的活化，而GPx8缺乏会导致caspase-4 / 11引起的结肠炎和败血性休克炎症。用小分子抑制caspase-4 / 11激活可降低GPx8缺陷小鼠结肠炎的严重程度。值得注意的是，溃疡性结肠炎患者的结肠组织显示出低水平的Gpx8和高表达的caspase-4。总之，这些结果表明，GPx8通过负调节caspase-4 / 11活性来预防结肠炎。