Journal
CELL
Volume 173, Issue 5, Pages 1123-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.04.037
Keywords
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Categories
Funding
- NIH [DK044319, DK053056, DK051362, DK088199, 5P01AI073748, DK102771]
- Harvard Digestive Diseases Center [P30DK034854]
- Crohn's and Colitis Foundation of America [383527, 418509]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI073748] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK053056, R01DK088199, K01DK102771, R01DK044319, R56DK053056, P30DK034854, R01DK051362, R37DK044319] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P40OD010995] Funding Source: NIH RePORTER
- BBSRC [BB/J016853/1, BBS/E/J/000PR9791] Funding Source: UKRI
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Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.
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