Publication Date:
2010-04-16
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796764/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796764/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buonocore, Sofia -- Ahern, Philip P -- Uhlig, Holm H -- Ivanov, Ivaylo I -- Littman, Dan R -- Maloy, Kevin J -- Powrie, Fiona -- 086354/Wellcome Trust/United Kingdom -- K99 DK085329/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Apr 29;464(7293):1371-5. doi: 10.1038/nature08949.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20393462" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, Ly/metabolism
;
Antigens, Thy-1/metabolism
;
Colitis/immunology/*pathology
;
Helicobacter Infections/immunology/pathology
;
Helicobacter hepaticus/immunology/pathogenicity
;
Immunity, Innate/*immunology
;
Interferon-gamma/immunology
;
Interleukin-17/immunology
;
Interleukin-23/*immunology
;
Intestines/*immunology/*pathology
;
Irritable Bowel Syndrome/immunology/pathology
;
Lymphoid Tissue/*cytology/*immunology
;
Membrane Proteins/metabolism
;
Mice
;
Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
;
Receptors, Interleukin/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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