title: Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation.
abstract: A plethora of functional and genetic studies have suggested a key role for the IL-23 pathway in chronic intestinal inflammation. Currently, pathogenic actions of IL-23 have been ascribed to specific effects on immune cells. Herein, we unveil a protective role of IL-23R signaling. Mice deficient in IL-23R expression in intestinal epithelial cells (Il23R(ΔIEC)) have reduced Reg3b expression, show a disturbed colonic microflora with an expansion of flagellated bacteria, and succumb to DSS colitis. Surprisingly, Il23R(ΔIEC) mice show impaired mucosal IL-22 induction in response to IL-23. αThy-1 treatment significantly deteriorates colitis in Il23R(ΔIEC) animals, which can be rescued by IL-22 application. Importantly, exogenous Reg3b administration rescues DSS-treated Il23R(ΔIEC) mice by recruiting neutrophils as IL-22-producing cells, thereby restoring mucosal IL-22 levels. The study identifies a critical barrier-protective immune pathway that originates from, and is orchestrated by, IL-23R signaling in intestinal epithelial cells.
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; First Medical Department, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Aden
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Ateequr
authors.initials: A
authors.lastname: Rehman
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Falk-Paulsen
authors.affiliation: University Toulouse, CNRS, Inserm, CHU Toulouse, UMR 1043-UMR 5282, Centre de Physiopathologie Toulouse Purpan, 31024 Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Secher
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Tran
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pfeuffer
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Sheibani-Tezerji
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Breuer
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Luzius
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Marlene
authors.initials: M
authors.lastname: Jentzsch
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Billmann-Born
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Will
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Lipinski
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Richa
authors.initials: R
authors.lastname: Bharti
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Timon
authors.initials: T
authors.lastname: Adolph
authors.affiliation: Aix-Marseille University, Institut Paoli-Calmettes, CNRS, Inserm, UMR 1068-UMR 7258, Centre de Recherche en Carcérologie de Marseille, 13273 Marseille, France.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kempster
authors.affiliation: Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; First Medical Department, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.affiliation: University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL, Centre d'Infection et d'Immunité de Lille, 59000 Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany. Electronic address: p.rosenstiel@mucosa.de.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D016264:Dextran Sulfate; D064806:Dysbiosis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D053759:Interleukin-23 / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D007518:Isoantibodies / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D000073718:Pancreatitis-Associated Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D000097043:Interleukin-22
chemical_list: D016264:Dextran Sulfate; D053759:Interleukin-23; D007378:Interleukins; D007518:Isoantibodies; D000073718:Pancreatitis-Associated Proteins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C490253:Reg3b protein, mouse; C035678:anti-Thy antibody; C528688:interleukin-23 receptor, mouse