Journal
NATURE
Volume 464, Issue 7293, Pages 1371-1375Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature08949
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Funding
- Wellcome Trust
- Marie-Curie Network [MRTN-CT2004-006532]
- Philippe Wiener-Maurice Anspach
- European Crohn's & Colitis Organisation (ECCO)
- European Commission [223151]
- Howard Hughes Medical Institute Exchange Programme
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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 (T(H)17) cells(1). Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells(2) 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-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gamma t 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-gamma t, 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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