Background and current state of research
The transcription factor Xbp1 is a key player of a conserved signalling network maintaining endoplasmic reticulum homeostasis, the Unfolded Protein Response (UPR). Considering that endoplasmic reticulum stress takes central stage in inflammatory bowel disease pathophysiology (Kaser & Blumberg, 2011), today it is not surprising that impairment of such a fundamental cellular function such as the UPR is also linked to IBD as Xbp1 has been established as a risk gene for both Colitis ulcerosa and Crohn’s disease (Kaser et al., 2008). Accordingly, perturbations in the Ire1α/Xbp1 signalling branch e.g. by defective autophagy result in broad intestinal inflammation (Tschurtschenthaler et al., 2017). Moreover, Xbp1-deficient mice perform worse when it comes to dealing with bacterial infection, for example if stressed with L. monocytogenes infection (Kaser et al., 2008).
In addition, further findings point towards a role for ER-stress and the Ire1α/Xbp1 network in directly regulating innate immune signalling (Liu et al., 2012; Zeng et al., 2010). However, the underlying mechanisms of the interplay of ER-stress and innate immunity in the gut remain elusive.
Given the previous work around ER-stress and innate immunity, we want to have a closer look on regulatory mechanisms and interacting pathways of Xbp1-signalling in the intestinal epithelium. Our work aims on resolving via which pathways Xbp1 might enforce its impact on innate immune responses. Therefore, based on previous data of our own and others (Liu et al., 2012; Zeng et al., 2010) we focus our efforts around type I interferon production and signalling.
How to get there
In order to gain a first insight into Xbp1 dependent regulatory mechanisms in innate immunity pathways, we will approach the issue using intestinal epithelial cell lines and murine small intestinal organoids deficient for Xbp1. Using these models, we hope to understand which role Xbp1 might play e.g. if cell lines or organoids are subjected to bacterial or viral infection. Afterwards, verification of infection experiments might take place using Xbp1ΔIEC knockout mice and other.
Kaser, A., & Blumberg, R. S. (2011). Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease. Gastroenterology, 140(6), 1738–1747.
Kaser, A., Lee, A.-H., Franke, A., Glickman, J. N., Zeissig, S., Tilg, H.,. . . Blumberg, R. S. (2008). XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 134(5), 743–756.
Liu, Y.-P., Zeng, L., Tian, A., Bomkamp, A., Rivera, D., Gutman, D.,. . . Smith, J. A. (2012). Endoplasmic reticulum stress regulates the innate immunity critical transcription factor IRF3. Journal of immunology (Baltimore, Md. : 1950), 189(9), 4630–4639.
Tschurtschenthaler, M., Adolph, T. E., Ashcroft, J. W., Niederreiter, L., Bharti, R., Saveljeva, S.,. . . Kaser, A. (2017). Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. The Journal of experimental medicine, 214(2), 401–422.
Zeng, L., Liu, Y.-P., Sha, H., Chen, H., Qi, L., & Smith, J. A. (2010). XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages. Journal of immunology (Baltimore, Md. : 1950), 185(4), 2324–2330.