Universität zu Köln

Kaya, Göksu Gökberk ORCID: 0000-0003-2976-9318 (2025). The Role of XBP1 in Necroptosis-Induced Intestinal Inflammation. PhD thesis, Universität zu Köln.

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Abstract

Intestinal epithelial cells (IECs) form an epithelial barrier which is covered and reinforced with the mucus layer. The intestinal epithelium and the mucus layer play critical roles in the regulation of intestinal immune homeostasis by establishing a stratified, protective barrier against luminal microbiota. Dysregulated epithelial cell death and a bacteria-permeable mucus layer were implicated in inflammatory bowel disease (IBD). While environmental factors including gut microbiota are thought to contribute to the disease pathology, the host’s genetic background is a significant determinant of predisposition to IBD. Specifically, hypomorphic variants of X-box binding protein 1 (XBP1), a gene encoding a critical transcription factor in response to endoplasmic reticulum (ER) stress, were identified in IBD patients. Meanwhile, humans deficient in caspase-8, a protein inhibiting necroptosis, were reported to develop intestinal inflammation. The polygenic risk score is a critical tool for assessing the predisposition to IBD, however, the crosstalk of multiple genetic variants and their pathways remains to be elucidated. In this study, we investigated the interaction between XBP1 deletion-induced ER stress and necroptosis triggered by the ablation of caspase-8 (Casp8) or Fas-associated with death domain (FADD) in IECs. Our results revealed that colitis but not ileitis in mice lacking epithelial-specific Casp8 or FADD was exaggerated by XBP1 deficiency. We showed that genetic inhibition of IEC necroptosis rescued the severe colitis in mice lacking XBP1 and Casp8 or XBP1 and FADD. IEC-derived Tumor necrosis factor (TNF) did not play an important role in the exacerbation of colitis, however, colitis was driven by epithelial-intrinsic TNF receptor 1 (TNFR1) in mice lacking XBP1 and Casp8. Importantly, we found that MUCIN-2 (MUC2), a gel-forming mucin crucially required for the formation of bacteria-impermeable mucus layer in the colon, was strongly downregulated in the colons of XBP1 deficient mice. Mice lacking XBP1 in IECs showed an intact intestinal epithelium covered by a dysfunctional mucus layer leading to increased contact between luminal bacteria and the apical regions of colonic epithelial cells. Whereas XBP1 deficiency-induced mucus barrier impairment did not culminate in spontaneous colon inflammation, it strongly synergised with epithelial necroptosis and exaggerated the colitis in mice lacking Casp8 or FADD. Furthermore, we showed that the impairment of the mucus layer in XBP1 deficiency was independent of extrinsic apoptosis and necroptosis of IECs. Taken together, this study revealed a hitherto unidentified link between ER stress, necroptosis and mucus layer in intestinal inflammation, which could contribute to understanding the pathogenesis of IBD.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Kaya, Göksu Gökberk gkaya2@uni-koeln.de orcid.org/0000-0003-2976-9318 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-789891
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language necroptosis UNSPECIFIED unfolded protein response UNSPECIFIED intestinal epithelial barrier UNSPECIFIED
Date of oral exam:	21 November 2024
Referee:	Name Academic Title Pasparakis, Manolis Prof. Dr. Kashkar, Hamid Prof. Dr. Rosenstiel, Philip Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78989