2. Academic Validation
  3. Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier

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

  • Immunity. 2025 Sep 9;58(9):2208-2225.e6. doi: 10.1016/j.immuni.2025.07.023.
Göksu Gökberk Kaya 1,  Robin Schwarzer 1,  Marius Dannappel 1,  Katerina Vlantis 1,  Ulrike Göbel 2,  Vangelis Kondylis 3,  Sergei A Nedospasov 4,  Manolis Pasparakis 5
Affiliations

Affiliations

  • 1 Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
  • 2 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
  • 3 Institute for Pathology, Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
  • 4 Engelhardt Institute of Molecular Biology, Moscow, Russia; Division of Immunobiology and Biomedicine, Sirius University of Science and Technology, Sirius, 354349 Krasnodarsky Krai, Russia.
  • 5 Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany. Electronic address: pasparakis@uni-koeln.de.
PMID: 40865520 DOI: 10.1016/j.immuni.2025.07.023
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.

Keywords

FADD; IRE1; XBP1; caspase-8; impaired mucus layer; inflammatory bowel disease; intestinal epithelial barrier; mucin 2; necroptosis; unfolded protein response.

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