Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology

Top Cited Papers
Open Access
Publisher Website
Google Scholar
Abstract
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-γ. 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-γ. 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 (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.