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Author(s): Sofia Buonocore [sup.1] , Philip P. Ahern [sup.1] , Holm H. Uhlig [sup.3] , Ivaylo I. Ivanov [sup.4] , Dan R. Littman [sup.4] , Kevin J. Maloy [sup.1] , [...], Innate intestinal inflammatory responses Interleukin 23 (IL-23) has been implicated in the pathogenesis of autoimmune and chronic inflammatory disorders. New work in a mouse model has identified a previously unrecognized population of innate lymphoid cells that respond to IL-23 by inducing inflammation through the production of IL-17 and interferon-[gamma]. Further work will be needed to establish whether this newly discovered IL-23-driven pathway contributes to chronic inflammatory diseases such as irritable bowel disease. The cytokine interleukin (IL)-23 has inflammatory effects on innate immune cells and can drive colitis, but the cellular and molecular pathways involved are poorly characterized. Here it is shown that bacterial-driven innate colitis involves a previously unknown population of IL-23-responsive innate leukocytes that produce IL-17 and interferon-[gamma]. These cells may represent a target in inflammatory bowel disease. 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.sub.H17) cells.sup.1. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells.sup.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.sup.-/-Rorc.sup.-/- mice failed to develop innate colitis. Last, depletion of Thy1.sup.+ 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.

Author(s): Nathaniel R West; Ahmed N Hegazy; Benjamin M J Owens; Samuel J Bullers; Bryan Linggi; Sofia Buonocore; Margherita Coccia; Dieter Görtz; Sébastien This; Krista Stockenhuber; Johanna Pott; Matthias Friedrich; [...]