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.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
MeSH terms
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Animals
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Colitis / chemically induced
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Colitis / drug therapy
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Colitis / immunology*
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Colitis / microbiology
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Dextran Sulfate
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Dysbiosis / drug therapy
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Dysbiosis / immunology*
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Dysbiosis / pathology
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Epithelial Cells / drug effects
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Epithelial Cells / immunology
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Epithelial Cells / microbiology
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Gene Expression Regulation
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Granulocytes / drug effects
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Granulocytes / immunology
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Granulocytes / microbiology
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Interleukin-22
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Interleukin-23 / pharmacology
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Interleukins / genetics
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Interleukins / immunology*
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Interleukins / pharmacology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / microbiology
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Isoantibodies / pharmacology
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Male
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Mice
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Mice, Knockout
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Neutrophils / drug effects
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Neutrophils / immunology
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Neutrophils / microbiology
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Pancreatitis-Associated Proteins / genetics
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Pancreatitis-Associated Proteins / immunology
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Pancreatitis-Associated Proteins / pharmacology
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Receptors, Interleukin / deficiency
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Receptors, Interleukin / genetics
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Receptors, Interleukin / immunology*
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Signal Transduction
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Stem Cells / drug effects
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Stem Cells / immunology
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Stem Cells / microbiology
Substances
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Interleukin-23
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Interleukins
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Isoantibodies
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Pancreatitis-Associated Proteins
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Receptors, Interleukin
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Reg3b protein, mouse
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anti-Thy antibody
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interleukin-23 receptor, mouse
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Dextran Sulfate