Abstract
T-bet(-/-).Rag2(-/-) (TRUC) mice spontaneously develop microbiota-driven, TNF-mediated large bowel inflammation that resembles human ulcerative colitis. We show here that IL-23 and IL-1-dependent secretion of IL-17A by innate lymphoid cells (ILCs; defined as CD45(+)lin(-)Thy1(hi)NKp46(-)) is a second critical pathway in this model. Using an in vitro coculture system of bone marrow-derived dendritic cells (DCs) and freshly isolated FACS-purified ILCs, we demonstrate that IL-23 and IL-1 secreted by DCs in response to microbial stimulation work together to induce IL-17A production by ILCs. TNF is not required for IL-17A secretion by ILCs in vitro but synergizes with IL-17A to induce the expression of neutrophil-attracting chemokines. Upstream, activation of the IL-23/IL-17A axis is regulated by nucleotide-binding oligomerization domain containing (Nod)/receptor-interacting serine-threonine kinase 2 (Ripk2) signals in DCs. Genetic ablation of the Nod/Ripk2 signaling pathway protects TRUC mice from developing colitis without affecting the colitogenicity of the intestinal microbiota. Our data provide insight into the complex network of interactions between IL-17A-secreting ILCs and other components of the innate immune system in the development of colitis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacteria / immunology
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Bone Marrow Cells / cytology
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Bone Marrow Cells / immunology*
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Chemokines / genetics
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Chemokines / immunology
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Colitis, Ulcerative / genetics
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Colitis, Ulcerative / immunology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology*
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Dendritic Cells / immunology*
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Dendritic Cells / pathology
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Humans
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-23 / genetics
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Interleukin-23 / immunology
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Intestines / immunology
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Intestines / microbiology
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Intestines / pathology
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Mice
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Mice, Knockout
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology*
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T-bet Transcription Factor
Substances
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Chemokines
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DNA-Binding Proteins
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Il17a protein, mouse
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Interleukin-17
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Interleukin-23
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Rag2 protein, mouse
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T-Box Domain Proteins
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T-bet Transcription Factor
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk2 protein, mouse