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

• IL-23R transduces signals into the intestinal epithelium
• Il23RΔIEC mice are susceptible to DSS colitis and have a disturbed gut microflora
• Epithelial IL-23R is required for optimal secretion of the c-type lectin Reg3b
• The c-type lectin Reg3b promotes recruitment of IL-22-producing cells as an alarmin
• Systemic substitution of Reg3b rescues the gut barrier defect of Il23RΔIEC mice

SummaryA 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 (Il23RΔIEC) have reduced Reg3b expression, show a disturbed colonic microflora with an expansion of flagellated bacteria, and succumb to DSS colitis. Surprisingly, Il23RΔIEC mice show impaired mucosal IL-22 induction in response to IL-23. αThy-1 treatment significantly deteriorates colitis in Il23RΔIEC animals, which can be rescued by IL-22 application. Importantly, exogenous Reg3b administration rescues DSS-treated Il23RΔIEC 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.

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