德国科隆大学Manolis Pasparakis小组取得一项新突破。他们的研究开发出了未折叠蛋白反应转录因子XBP1通过加强粘液屏障抑制坏死性结肠炎。相关论文于2025年8月26日发表于国际顶尖学术期刊《免疫学》杂志上。

研究人员发现，在肠上皮细胞（IEC）特异性X-box结合蛋白1 （XBP1）缺乏的小鼠中，caspase-8或其与死亡结构域（FADD）相关的适配器Fas缺乏，会强烈加剧坏死性凋亡诱导的结肠炎的发展，但不会加剧回肠炎。从机制上讲，XBP1消融导致结肠黏液蛋白2 （MUC2）表达减少和黏液层形成受损，这使得细菌能够穿透并到达上皮表面。在完整的上皮单层存在的情况下，这不足以引发结肠炎，但与IEC坏死性坏死协同作用可诱导严重的结肠炎症。他们的研究结果表明，XBP1和caspase-8控制肠道屏障的不同成分，这些成分协同维持粘膜免疫稳态并预防结肠炎症。这可能与更好地理解IBD的机制有关。

研究人员表示，内质网应激和坏死性下垂与炎症性肠病（IBD）的发病机制有关；然而，这些途径之间潜在的串扰尚不清楚。

附：英文原文

Title: Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier

Author: Gksu Gkberk Kaya, Robin Schwarzer, Marius Dannappel, Katerina Vlantis, Ulrike Gbel, Vangelis Kondylis, Sergei A. Nedospasov, Manolis Pasparakis

Issue&Volume: 2025-08-26

Abstract: Endoplasmic reticulum (ER) stress and necroptosis are associated with the pathogenesis of inflammatory bowel disease (IBD); however, the potential crosstalk between these pathways is unclear. Here, we show that intestinal epithelial cell (IEC)-specific X-box binding protein 1 (XBP1) deficiency strongly aggravates the development of necroptosis-induced colitis, but not ileitis, in mice lacking caspase-8 or its adapter Fas associated with death domain (FADD) in IECs. Mechanistically, XBP1 ablation led to diminished mucin 2 (MUC2) expression and impaired mucus layer formation in the colon, which allowed bacteria to penetrate and reach the epithelial surface. This was not sufficient to trigger colitis in the presence of an intact epithelial monolayer but synergized with IEC necroptosis to induce severe colon inflammation. Our results revealed that XBP1 and caspase-8 control different components of the intestinal barrier that synergize to maintain mucosal immune homeostasis and prevent colon inflammation. This could be relevant for the better understanding of the mechanisms causing IBD.

DOI: 10.1016/j.immuni.2025.07.023

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00332-2