Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
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) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells 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)-gammat 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-gammat, 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.
Buonocore
Sofia
S
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
Ahern
Philip P
PP
Uhlig
Holm H
HH
Ivanov
Ivaylo I
II
Littman
Dan R
DR
Maloy
Kevin J
KJ
Powrie
Fiona
F
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D003092:Colitis / Q000276:immunology / Q000473:pathology*; D016481:Helicobacter Infections / Q000276:immunology / Q000473:pathology; D044923:Helicobacter hepaticus / Q000276:immunology / Q000472:pathogenicity; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000473:pathology*; D043183:Irritable Bowel Syndrome / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000166:cytology* / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D018800:Thy-1 Antigens / Q000378:metabolism
D000950:Antigens, Ly; D020381:Interleukin-17; D053759:Interleukin-23; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018123:Receptors, Interleukin; D018800:Thy-1 Antigens; C528688:interleukin-23 receptor, mouse; D007371:Interferon-gamma
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