Mechanisms linking IFN-mediated cell death with bile acid signaling in small intestinal inflammation
Project Summary
Although interferons (IFNs) act at mucosal surfaces, the molecular mechanisms underlying their mucosal functions are still poorly understood. Our unpublished data suggest that IFN-induced programmed necrosis plays a key role in the pathogenesis of intestinal inflammation. Accordingly, IFNs promote non-apoptotic epithelial cell death, upregulation of the mixed lineage kinase domain-like protein, and disruption of immune homeostasis. The central question of this project is whether, and through which pathways, epithelial IFN-regulated necrosis contributes to intestinal inflammation. We aim to uncover new functions of IFNs in immune-epithelial communication that could become targets for future therapeutic interventions.
Selected project-relevant publications
Roth D, Düll MM, Horst LJ, Lindemann A, Malzer X, Koop K, Zundler S, Vetter M, Jefremow A, Atreya R, Geppert C, Weidemann S, Waldner MJ, Dietrich P, Günther C, Munoz LE, Herrmann M, Scheffold A, Neurath MF, Siebler J, Schramm C, Kremer AE, Leppkes M.
Integrin αVβ6: Autoantigen and Driver of Epithelial Remodeling in Colon and Bile Ducts in Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.
J Crohns Colitis. 2025 Feb 4;19(2):jjae131. doi: 10.1093/ecco-jcc/jjae131.
Gonzalez-Acera M, Patankar JV, Erkert L, Cineus R, Gamez-Belmonte R, Leupold T, Bubeck M, Bao LL, Dinkel M, Wang R, Schickedanz L, Limberger H, Stolzer I, Gerlach K, Diemand L, Mascia F, Gupta P, Naschberger E, Koop K, Plattner C, Sturm G, Weigmann B, Günther C, Wirtz S, Stürzl M, Hildner K, Kühl AA, Siegmund B, Gießl A, Atreya R; TRR241 IBDome Consortium; Hegazy AN, Trajanoski Z, Neurath MF, Becker C.
Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD.
Gut. 2025 Apr 29:gutjnl-2024-333729. doi: 10.1136/gutjnl-2024-333729.
Erkert L, Ruder B, Kabisch M, Gamez Belmonte R, Patankar JV, Gonzalez Acera M, Schödel L, Chiriac MT, Cineus R, Gnafakis S, Leupold T, Thoma OM, Stolzer I, Taut A, Thonn V, Zundler S, Günther C, Diefenbach A, Kühl AA, Hegazy AN, Waldner M, Basic M, Bleich A, Neurath MF, Wirtz S, Becker C; TRR241 IBDome Consortium.
TIFA renders intestinal epithelial cells responsive to microbial ADP-heptose and drives colonic inflammation in mice.
Mucosal Immunol. 2025 Apr;18(2):453-466. doi: 10.1016/j.mucimm.2025.01.003.
Dorner H, Stolzer I, Mattner J, Kaminski S, Leistl S, Edrich LM, Schwendner R, Hobauer J, Sebald A, Leikam S, Gonzalez Acera M, Düll M, Lang R, Seidel G, Seitz T, Hellerbrand C, Fuhrmann G, Distler U, Tenzer S, Eichhorn P, Vieth M, Schramm C, Arnold P, Becker C, Weidinger C, Siegmund B, Atreya R, Leppkes M, Naschberger E, Sampaziotis F, Dietrich P, Rauh M, Wirtz S, Kremer AE, Neurath MF, Günther C.
Gut Pathobiont-Derived Outer Membrane Vesicles Drive Liver Inflammation and Fibrosis in Primary Sclerosing Cholangitis-Associated Inflammatory Bowel Disease.
Gastroenterology. 2024 Nov;167(6):1183-1197.e16. doi: 10.1053/j.gastro.2024.06.032. Epub 2024 Jul 9. PMID: 38992449.
Chiriac MT, Hracsko Z, Günther C, Gonzalez-Acera M, Atreya R, Stolzer I, Wittner L, Dressel A, Schickedanz L, Gamez-Belmonte R, Erkert L, Hundorfean G, Zundler S, Rath T, Vetrano S, Danese S, Sturm G, Trajanoski Z, Kühl AA, Siegmund B, Hartmann A, Wirtz S, Siebler J, Finotto S, Becker C, Neurath MF.
IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling.
Gut. 2024 Jan 5;73(2):282-297. doi: 10.1136/gutjnl-2023-329628. PMID: 37884352; PMCID: PMC10850655.
Wiendl M, Dedden M, Liu LJ, Schweda A, Paap EM, Ullrich KA, Hartmann L, Wieser L, Vitali F, Atreya I, Müller TM, Günther C, Atreya R, Neurath MF, Zundler S.
Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells.
Nat Commun. 2024 Feb 3;15(1):1043. doi: 10.1038/s41467-024-45352-6. PMID: 38310086; PMCID: PMC10838339.
Naschberger E, Fuchs M, Dickel N, Kunz M, Popp B, Anchang CG, Demmler R, Lyu Y, Uebe S, Ekici AB, Geppert CI, Hartmann A, Flierl C, Petter K, Gass T, Völkl S, Scharl M, Ramming A, Günther C, Merkel S, Schellerer VS, Stürzl M.
Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome.
Cancer Commun (Lond). 2023 Nov;43(11):1280-1285. doi: 10.1002/cac2.12489. Epub 2023 Oct 19. PMID: 37859581; PMCID: PMC10631479.
Wittner L, Wagener L, Wiese JJ, Stolzer I, Krug SM, Naschberger E, Jackstadt R, Beyaert R, Atreya R, Kühl AA, Sturm G, Gonzalez-Acera M, Patankar JV, Becker C, Siegmund B, Trajanoski Z, Winner B, Neurath MF, Schumann M, Günther C.
Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing.
Int J Mol Sci. 2023 Apr 17;24(8):7402. doi: 10.3390/ijms24087402. PMID: 37108564; PMCID: PMC10138456.
Schneider I, Allner C, Mühl L, Melde M, Lissner D, Mantzivi E, Glauben R, Vitali F, Becker E, Atreya I, Müller TM, Atreya R, Siegmund B, Neurath MF, Zundler S.
Expression and function of α4β7 integrin predict the success of vedolizumab treatment in inflammatory bowel disease.
Transl Res. 2023 Mar;253:8-15. doi: 10.1016/j.trsl.2022.10.003. Epub 2022 Oct 20. PMID: 36272713.
Martínez-Sánchez LDC, Ngo PA, Pradhan R, Becker LS, Boehringer D, Soteriou D, Kubankova M, Schweitzer C, Koch T, Thonn V, Erkert L, Stolzer I, Günther C, Becker C, Weigmann B, Klewer M, Daniel C, Amann K, Tenzer S, Atreya R, Bergo M, Brakebusch C, Watson AJM, Guck J, Fabry B, Atreya I, Neurath MF, López-Posadas R.
Epithelial RAC1-dependent cytoskeleton dynamics controls cell mechanics, cell shedding and barrier integrity in intestinal inflammation.
Gut. 2023 Feb;72(2):275-294. doi: 10.1136/gutjnl-2021-325520. Epub 2022 Mar 3. PMID: 35241625; PMCID: PMC9872254.