Abstract
The interleukin-23 (IL-23) pathway has emerged as a promising therapeutic target for inflammatory bowel disease. Although the pathogenic role of IL-23 receptor (IL-23R) on T lymphocytes is well established, its function on innate immune cells has not been thoroughly examined. Here we investigate the consequence of IL-23R deletion in dextran sulfate sodium (DSS)-induced colitis. In IL23R(-/-) and IL23p19(-/-) mice, we observed decreased weight loss and reduced leukocyte infiltrate following DSS exposure. Surprisingly, when the IL-23R(-/-) allele was crossed into Rag2(-/-) mice, we observed exacerbated disease, increased epithelial damage, reduced pSTAT3 in the epithelium, and delayed recovery of IL23R(-/-)Rag2(-/-) mice. This phenotype was rescued with exogenous IL22-Fc, and epithelial pSTAT3 was restored. Depletion of Thy1(+) innate lymphoid cells eliminated the majority of IL-22 production in the colon lamina propria of DSS-treated Rag2(-/-) mice, suggesting that these are the major IL-23 responsive innate cells in this context. In summary, we provide evidence for opposing consequences of IL-23R on innate and adaptive lymphoid cells in murine colitis.
MeSH terms
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Adaptive Immunity
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Animals
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Cell Movement / drug effects
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Cell Movement / genetics
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Colitis / chemically induced
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Colitis / immunology*
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DNA-Binding Proteins / genetics
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Dextran Sulfate / administration & dosage
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Disease Models, Animal
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Humans
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Immunity, Innate
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Inflammatory Bowel Diseases / immunology*
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Interleukin-22
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Interleukin-23 Subunit p19 / genetics
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Interleukin-23 Subunit p19 / immunology
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Interleukin-23 Subunit p19 / metabolism*
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Interleukins / antagonists & inhibitors
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism*
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Intestinal Mucosa / pathology
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Lymphocyte Depletion
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Mice
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Mice, Knockout
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Receptors, Interleukin / genetics
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Receptors, Interleukin / metabolism*
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Recombinant Fusion Proteins / administration & dosage
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
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Weight Loss / drug effects
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Weight Loss / genetics
Substances
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DNA-Binding Proteins
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Interleukin-23 Subunit p19
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Interleukins
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Rag2 protein, mouse
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Receptors, Interleukin
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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interleukin-23 receptor, mouse
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Dextran Sulfate