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

Abstract

The key role of IL-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23R susceptibility alleles associated with IBD, psoriasis and ankylosing spondylitis. IL-23 driven inflammation has primarily been linked to the actions of 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 increased IL-17 and IFN-γ production in the colon. Stimulation of colonic leukocytes with IL-23 induced IL-17 and IFN-γ production exclusively by innate lymphoid cells expressing Thy1, SCA-1, RORγt and IL-23R and these cells markedly accumulated in the inflamed colon. Importantly, IL-23 responsive innate intestinal cells are also a feature of T-cell dependent models of colitis. The transcription factor RORγt, which controls IL-23R expression, plays a functional role as Ror−/−Rag−/− mice failed to develop innate colitis. Lastly, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a novel IL-23 responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in IBD.

RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

“…Thus, whereas during steady state, microbiota, T H 17 and RORγt + ILCs are controlled by a complex regulatory network, during tissue damage and consequent inflammation, both adaptive and innate RORγt + cells add up production of IL-22 to force a return to homeostasis. However, such situations are potentially dangerous to the host, as the pro-inflammatory activity of T H 17 cells and RORγt + ILCs may expand beyond control and induce inflammatory pathology [54][55][56] . …”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…However, chronic activation of ILC3 can result in disease due to uncontrolled inflammation. ILC3 drive colitis in an innate anti‐CD40 driven model of colitis and during Helicobacter hepaticus infection in an IL‐23‐dependent manner, which has been associated with production of GM‐CSF and IFN‐ γ by pro‐inflammatory ILC3 71, 118, 128, 129. Neonatal ILC3 can also mediate intestinal pathology in response to transgenic over‐expression of IL‐23 through the release of IL‐17A, IL‐22, IFN‐ γ and GM‐CSF 130.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…There also seems to be some plasticity between ILC1 and ILC3 cells 32, 33. Thus, ILCs secreting both IFN γ and IL‐17 in response to IL‐23, or IFN γ and IL‐22 in response to IL‐12+IL‐18 have been reported 26, 34. It is thought that both NK cells and ILC1s depend on IL‐15 for their development,35, 36, 37, 38 which is in contrast to ILC2s and ILC3s, which rely on IL‐7 and are depleted in IL‐7R α −/− mice 19, 39…”