Abstract
Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22-responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti-IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / immunology
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Citrobacter rodentium / immunology
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Colitis / genetics
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Colitis / immunology
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Colon / immunology*
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Colon / metabolism
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Dextran Sulfate / adverse effects
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Enterobacteriaceae Infections / genetics
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Enterobacteriaceae Infections / immunology
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Enterobacteriaceae Infections / metabolism
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Inflammation / genetics
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Inflammation / immunology*
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Inflammation / metabolism
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Interleukin-22
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Interleukins / biosynthesis
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Interleukins / genetics
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Interleukins / immunology*
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Lymphocytes / immunology*
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Lymphocytes / metabolism
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Mice
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Mice, Inbred C57BL
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Protein Binding / genetics
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Protein Binding / immunology
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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Receptors, Antigen, T-Cell, gamma-delta / immunology*
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Receptors, Antigen, T-Cell, gamma-delta / metabolism
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Receptors, Retinoic Acid / immunology
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Receptors, Retinoic Acid / metabolism
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T-Lymphocytes, Helper-Inducer / immunology*
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T-Lymphocytes, Helper-Inducer / metabolism
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Transcription, Genetic / genetics
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Transcription, Genetic / immunology
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Tretinoin / immunology*
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Tretinoin / metabolism
Substances
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Antibodies, Neutralizing
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Interleukins
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Receptors, Antigen, T-Cell, gamma-delta
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Receptors, Retinoic Acid
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Tretinoin
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Dextran Sulfate