We investigate the mechanisms that underlie inflammation at mucosal surfaces.
A single layer of intestinal epithelial cells – which may be considered the evolutionary most ancient innate immune cell type – separates the complex and densely populated habitat of the microbiota from the sterile host tissue of the gut, which itself harbours the majority of the host's bona fide immune cells. A loss of the mutualistic relationship between host and microbiota is thought to be at the basis of the inflammatory bowel diseases Crohn's disease and ulcerative colitis.
Using a variety of techniques, including complex genetic models, we explore the major biological mechanisms that are affected by risk genes of inflammatory bowel disease. This approach opens up a window to explore the environmental factors that may trigger disease in genetically susceptible individuals, and which are the cause for the steep increase in incidence and prevalence of these diseases around the world. Following this path, we have reported mechanisms of how hypomorphic autophagy and mediators of the unfolded protein response lead to inflammatory bowel disease, defining a key pathway of Crohn's disease pathogenesis. Further following this paradigm, we have more recently discovered an entirely novel immunometabolic pathway that determines risk for Crohn's disease, leprosy, and systemic juvenile idiopathic arthritis.
Tschurtschenthaler M, Adolph TE, Ashcroft JW, Niederreiter L, Bharti R, Saveljeva S, Bhattacharyya J, Flak MB, Shih DQ, Fuhler GM, Parkes M, Kohno K, Iwawaki T, van der Woude CJ, Harding HP, Smith AM, Peppelenbosch MP, Targan SR, Ron D, Rosenstiel P, Blumberg RS, Kaser A. Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. J Exp Med 2017 Jan; doi: 10.1084/jem.20160791.
Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL, Sewell GW, Saveljeva S, Ashcroft JW, Clare S, Mukhopadhyay S, Brown KP, Tschurtschenthaler M, Raine T, Doe B, Chilvers ER, Griffin JL, Kaneider NC, Floto RA, D'Amato M, Bradley A, Wakelam MJO, Dougan G, Kaser A. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol 2016 Sep;17(9):1046-56. doi: 10.1038/ni.3532. Epub 2016 Aug 1.
Tschurtschenthaler M, Kachroo P, Heinsen FA, Adolph TE, Rühlemann MC, Klughammer J, Offner FA, Ammerpohl O, Krueger F, Smallwood S, Szymczak S, Kaser A*, Franke A*. Paternal chronic colitis causes epigenetic inheritance of susceptibility to colitis. Sci Rep 2016 Aug 19;6:31640. doi: 10.1038/srep31640. * shared senior and communicating authors
Wieser V, Adolph TE, Enrich B, Kuliopulos A, Kaser A, Tilg H, Kaneider NC. Reversal of murine alcoholic steatohepatitis by pepducin-based functional blockade of interleukin-8 receptors. Gut 2016 Feb 8. pii: gutjnl-2015-310344. doi: 10.1136/gutjnl-2015-310344.
Adolph TE†, Tomczak MF†, Niederreiter L†, Ko H-J†, Böck J, Martinez-Naves E, Glickman JN, Tschurtschenthaler M, Hartwig J, Hosomi S, Flak MB, Cusick JL, Kohno K, Iwawaki T, Billmann-Born S, Raine T, Bharti R, Lucius R, Kweon M-N, Marciniak SJ, Choi A, Hagen SJ, Schreiber S, Rosenstiel P, Kaser A* & Blumberg RS*. Paneth cells as a site of origin for intestinal inflammation. Nature 2013 Nov 14;503(7475):272-6. doi: 10.1038/nature12599. Epub 2013 Oct 2. † shared first authors, * shared senior and communicating authors
Niederreiter L, Fritz TMJ, Adolph TE, Krismer A-M, Offner FA, Tschurtschenthaler M, Flak, MB, Hosomi, S, Tomczak MF, Kaneider NC, Sarcevic E, Kempster SL, Raine T, Esser, D, Roaenstiel P, Kohno K, Iwawaki T, Tilg H, Blumberg RS & Kaser A. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med 2013; 210 (10): 2041
Olszak T, Neves JF, Dowds CM, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K, Wada K, Katayama K, Nakajima A, Mizuguchi H, Kawasaki K, Nagata K, Müller W, Snapper SB, Schreiber S, Kaser A, Zeissig S, Blumberg RS. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature 2014 May 22;509(7501):497-502.
Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743-56.