XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease
By A. Kaser, Ann-Hwee Lee, Andre Franke, J. Glickman, S. Zeissig, Herbert Tilg, E. Nieuwenhuis, D. Higgins, Stefan Schreiber, Laurie H. Glimcher and 1 more. Cell, 2008
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Summary Inflammatory bowel disease (IBD) has been attributed to aberrant mucosal immunity to the intestinal microbiota. The transcription factor XBP1, a key component of the endoplasmic reticulum (ER) stress response, is required for development and maintenance of secretory cells and linked to JNK activation. We report that XBP1 deletion in intestinal epithelial cells (IEC) results in spontaneous enteritis and increased susceptibility to induced colitis secondary to both Paneth cell deficiency and overactive responses of the intestinal epithelial cell (IEC) to the IBD-inducers, TNFα and flagellin. An association of XBP1 variants with human IBD was identified and replicated (rs35873774, P-value 1.6×10−5) with novel, private hypomorphic variants identified as susceptibility factors. Hence, intestinal inflammation can originate solely from XBP1 abnormalities in IEC thus linking cell-specific ER stress to the induction of organ-specific inflammation. We report the first mouse model of spontaneous intestinal inflammation arising from alterations in a genetic risk factor for human IBD.
Subfields: Cell Biology, Immunology, Speech and Hearing
View Paper: https://www.semanticscholar.org/paper/b0bfd070848ea12cf7dd4dafff4f01f006ccd733
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Citations in the corpus
- Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. (2013, background): “Within 24 hr, red fluorescence indicating recombination was detectable in IEC above the crypt villus junction as well as in Paneth cells, a cell type in which XBP splicing confers important functions (Kaser et al., 2008) (Figures 6A and 6B).”
- ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, background): “…the induction of XBP1’s activity occurs at the same time that the NFKB1/REL/RELA activity stops increasing, which is in line with studies showing that the UPR can attenuate the induction of inflammation as mediated by TFs of the NFkappaB family (Kaser et al. 2008; Kitamura 2011; Li et al. 2011).”
- The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system (2014, neutral): “This stress placed on the ER is probably also the reason for the relationship between ER stress, the unfolded protein response and colonic inflammation, something that has been discussed in detail elsewhere (20, 70, 71).”
- ER stress-induced cell death mechanisms. (2013, background): “[78] reported that XBP-1 deletion in intestinal epithelial cells (IEC) results in spontaneous enteritis and overactive responses of IECs to IBD inducers, TNFα and flagellin.”
- New IBD genetics: common pathways with other diseases (2011, background): “Xbp1 mice (intestinal epithelial cell specific deletion of Xbp1) demonstrate increased ER stress, develop spontaneous mild, patchy mucosal inflammation, and lack Paneth cells.(153) ER stress is increased in intestinal epithelial cells in patients with active IBD, and IL-10 inhibits inflammationinduc”
- Innate and adaptive immunity in inflammatory bowel disease. (2014, background): “Consistently, specific deletion of XBP1 in the intestinal epithelial cell compartment results in small intestinal inflammation and increased susceptibility to dextran sulfate sodium colitis in mice [40].”