Abstract
The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells1. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells2 and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-γ exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-γt and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-γt, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.
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Change history
29 April 2010
Small changes were made to the labelling of Figs 2b, 3b and 4d.
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Acknowledgements
We thank N. Rust for cell sorting; R. Stillion and M. Ziegler for histology; J. Langhorne for providing the AN18 hybridoma; S. Cobbold and H.Waldmann for the gift of the depleting anti-Thy1 and isotype control antibodies; UCB Celltech for providing the blocking anti-IL-17 and isotype control antibodies; O. Boulard and S. Kirchberger for technical assistance; and C. Arancibia for critically reading the manuscript. This work was supported by the Wellcome Trust (F.P. and K.J.M.), the Marie-Curie Network fellowship (IMDEMI, MRTN-CT2004-006532) (S.B., P.A.), the Philippe Wiener-Maurice Anspach foundation (S.B.), European Crohn’s & Colitis Organisation (ECCO) (S.B.), the European Commission research programme INFLA-CARE (EC contract no. 223151) (S.B. and P.A.) and a Wellcome Trust and Howard Hughes Medical Institute Exchange Programme grant (P.A., F.P. and D.R.L.).
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S.B. and P.A. designed and performed the experiments. H.U. performed histology. I.I.I. and D.R.L. provided Rag-/-Rorc-/- mice and were involved in the experiments with this strain. S.B. wrote the manuscript with K.J.M. and F.P., and K.J.M. and F.P. directed the research.
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Competing interests: Collaboration with Celltech.
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This file contains Supplementary Methods and References and Supplementary Figures 1-12 with legends. Please note that the Supplementary Methods and References were added on April 18, 2010. (PDF 1474 kb)
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Buonocore, S., Ahern, P., Uhlig, H. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010). https://doi.org/10.1038/nature08949
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DOI: https://doi.org/10.1038/nature08949
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