Epithelial IL-23R Signaling Licenses Protective IL-22 Responses in Intestinal Inflammation.

Authors:
Konrad Aden, Ateequr Rehman, Maren Falk-Paulsen, Thomas Secher, Jan Kuiper, Florian Tran, Steffen Pfeuffer, Raheleh Sheibani-Tezerji, Alexandra Breuer, Anne Luzius, Marlene Jentzsch, Robert Häsler, Susanne Billmann-Born, Olga Will, Simone Lipinski, Richa Bharti, Timon Adolph, Juan L Iovanna, Sarah L Kempster, Richard S Blumberg, Stefan Schreiber, Burkhard Becher, Mathias Chamaillard, Arthur Kaser, Philip Rosenstiel
Year of publication:
2016
Volume:
16
Issue:
8
Issn:
2211-1247
Journal title abbreviated:
CELL REP
Journal title long:
Cell reports
Impact factor:
8.282
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.