Universität zu Köln

Kaya, Göksu Gökberk ORCID: 0000-0003-2976-9318, Schwarzer, Robin ORCID: 0009-0000-8139-2891, Dannappel, Marius ORCID: 0009-0009-6764-8278, Vlantis, Katerina ORCID: 0000-0002-7347-1589, Göbel, Ulrike, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Nedospasov, Sergei A. and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2025). Unfolded protein response transcription factor XBP1 suppresses necroptosis-induced colitis by reinforcing the mucus barrier. Immunity, 58 (9). 2208-2225.e6. Elsevier. ISSN 1074-7613

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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 under- standing of the mechanisms causing IBD.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Kaya, Göksu Gökberk UNSPECIFIED https://orcid.org/0000-0003-2976-9318 UNSPECIFIED Schwarzer, Robin UNSPECIFIED https://orcid.org/0009-0000-8139-2891 UNSPECIFIED Dannappel, Marius UNSPECIFIED https://orcid.org/0009-0009-6764-8278 UNSPECIFIED Vlantis, Katerina UNSPECIFIED https://orcid.org/0000-0002-7347-1589 UNSPECIFIED Göbel, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED https://orcid.org/0000-0002-6970-8731 UNSPECIFIED Nedospasov, Sergei A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED https://orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-806656
Identification Number:	10.1016/j.immuni.2025.07.023
Journal or Publication Title:	Immunity
Volume:	58
Number:	9
Page Range:	2208-2225.e6
Number of Pages:	25
Date:	9 September 2025
Publisher:	Elsevier
ISSN:	1074-7613
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80665