Intestinal NF-κB pathway-mediated pyroptosis contributes to endotoxemia-induced intestinal injury

Pyroptosis contributes to activation of the innate immunity system and defense against infection by pathogens. Endotoxemia is the host inflammatory storm occurring in response to severe and life-threatening infections caused by endotoxin from gram-negative bacilli. However, whether pyroptosis is involved in intestinal epithelial cell (IEC) or intestinal stem cell (ISC) injury induced by endotoxemia remains unclear. Mice with NF-κB p65 deletion in IECs (p65^IEC - KO) were used to investigate the role of NF-κB-mediated pyroptosis in endotoxemia-induced intestinal injury. Morphology, pyroptosis, permeability, inflammation, endoplasmic reticulum stress in the intestine and survival were evaluated in WT and p65^IEC - KO mice. Pyroptosis was found in intestinal epithelial cells of mice treated with lipopolysaccharide (LPS), but was significantly reduced in p65^IEC - KO mice. Mice with endotoxemia exhibited morphological alterations in intestinal tissue, with a shortened villus length and crypt depth, increased intestinal permeability, increased inflammatory factors, and reduced survival rate, all of which were markedly improved in p65^IEC - KO mice. Importantly, ER stress was found to be downregulated in IECs of p65^IEC - KO mice with endotoxemia. Furthermore, the ER stress activator tunicamycin markedly enhanced IEC pyroptosis and aggravated intestinal injury in p65^IEC - KO mice with endotoxemia. NF-κB p65-mediated pyroptosis participates in IEC injury in response to endotoxemia via regulation of ER stress. It may provide a potential therapeutic target for protecting against endotoxemia-induced intestinal injury.