title: c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine.
abstract: c-Jun N-terminal kinases (JNKs) contribute to immune signaling but their functional role during intestinal mucosal inflammation has remained ill defined. 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 analyzed 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 wild-type or JNK2-deficient mouse intestinal organoid cultures. We show that nonhematopoietic 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 expression, goblet cell and enteroendocrine cell differentiation, and mucus production under inflammatory conditions. Our results identify a protective role of epithelial JNK2 signaling to maintain mucosal barrier function, epithelial cell integrity, and mucus layer production in the event of inflammatory tissue damage.
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: A D
authors.initials: AD
authors.lastname: Mandić
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Bennek
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Verdier
authors.affiliation: Department of Microbiology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Roubrocks
authors.affiliation: Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Interdisciplinary Center for Clinical Research (IZKF), University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Denecke
authors.affiliation: Institute of Pathology, Klinikum Braunschweig, Braunschweig, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Streetz
authors.affiliation: GeneXplain GmbH, Wolfenbüttel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kel
authors.affiliation: Department of Microbiology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hornef
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: F J
authors.initials: FJ
authors.lastname: Cubero
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Sellge
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival; D003092:Colitis / Q000276:immunology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D020895:Enterocytes / Q000502:physiology*; D020397:Goblet Cells / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D007422:Intestines / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016264:Dextran Sulfate; D048056:Mitogen-Activated Protein Kinase 9