Wang Xinrui, Lu Wen, Cai Ruibin, Jiang Jie, Wang Chuyue, Liao Jinli, Zhang Yongshu, Li Danni, Ye Zi, Long Ming, Liu Zhihao
Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital of Sun Yat-sen University, No.58, Zhongshan 2nd Road, Guangzhou, 510080, China.
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No.600, Tianhe Road, Guangzhou, 510360, China.
Inflamm Res. 2025 Jun 30;74(1):94. doi: 10.1007/s00011-025-02064-x.
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) 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 mice. Pyroptosis was found in intestinal epithelial cells of mice treated with lipopolysaccharide (LPS), but was significantly reduced in p65 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 mice. Importantly, ER stress was found to be downregulated in IECs of p65 mice with endotoxemia. Furthermore, the ER stress activator tunicamycin markedly enhanced IEC pyroptosis and aggravated intestinal injury in p65 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.
细胞焦亡有助于激活先天性免疫系统并抵御病原体感染。内毒素血症是宿主针对革兰氏阴性杆菌内毒素引起的严重且危及生命的感染而发生的炎症风暴。然而，细胞焦亡是否参与内毒素血症诱导的肠上皮细胞（IEC）或肠干细胞（ISC）损伤仍不清楚。利用IEC中NF-κB p65缺失的小鼠（p65小鼠）来研究NF-κB介导的细胞焦亡在内毒素血症诱导的肠道损伤中的作用。评估了野生型（WT）和p65小鼠肠道的形态、细胞焦亡、通透性、炎症、内质网应激及生存率。在用脂多糖（LPS）处理的小鼠的肠上皮细胞中发现了细胞焦亡，但在p65小鼠中显著减少。内毒素血症小鼠的肠道组织出现形态学改变，绒毛长度缩短、隐窝深度变浅、肠道通透性增加、炎症因子增多且生存率降低，而在p65小鼠中所有这些均得到明显改善。重要的是，在内毒素血症的p65小鼠的IEC中发现内质网应激下调。此外，内质网应激激活剂衣霉素显著增强了p65内毒素血症小鼠的IEC细胞焦亡并加重了肠道损伤。NF-κB p65介导的细胞焦亡通过调节内质网应激参与内毒素血症诱导的IEC损伤。它可能为预防内毒素血症诱导的肠道损伤提供一个潜在的治疗靶点。
