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* = Presenting author

P041 C-jun n-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine

Mandić A.D.1, Bennek E.1, Verdier J.1, Zhang K.2, Roubrocks S.1, Davis R.J.3, Denecke B.4, Gassler N.5, Streetz K.6, Kel A.7, Hornef M.2, Cubero F.J.1, Trautwein C.1, Sellge G.*1

1University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany 2University Hospital RWTH Aachen, Department of Microbiology, Aachen, Germany 3Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, United States 4University Hospital RWTH Aachen, Interdisciplinary Center for Clinical Research (IZKF), Aachen, Germany 5Klinikum Braunschweig, Institute of Pathology, Braunschweig, Germany 6Gemeinschaftsklinikum Mittelrhein - Kemperhof, Department of Gastroenterology, Kobelnz, Germany 7geneXplain GmbH, Wolfenbüttel, Germany

Background

c-Jun N-terminal kinases (JNKs) contribute to immune signalling but their functional role during intestinal mucosal inflammation has remained ill defined

Methods

Using genetic mouse models we characterized the role of JNK1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation and barrier function were analysed in intestinal epithelium-specific (ΔIEC) or complete JNK1 and bone-marrow chimeric or complete JNK2 deficient mice as well as double knockout animals (JNK1ΔIECJNK2−/−) during homeostasis and acute dextran sulfate sodium (DSS)-induced colitis. Results were confirmed using human HT-29 cells and wildtype (WT) or JNK2 deficient mouse intestinal organoid cultures.

Results

We show that non-hematopoetic JNK2 but not JNK1 expression confers protection from DSS-induced intestinal inflammation reducing epithelial barrier dysfunction and enterocyte apoptosis. JNK2 additionally enhanced Atonal homolog 1 (Atoh1) expression, goblet cell and enteroendocrine cells differentiation and mucus production under inflammatory conditions.

Conclusion

Our results identify a protective role of epithelial JNK2 signalling to maintain mucosal barrier function, epithelial cell integrity and mucus layer production in the event of inflammatory tissue damage.