Cell
Volume 173, Issue 5, 17 May 2018, Pages 1123-1134.e11
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Article
Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses

https://doi.org/10.1016/j.cell.2018.04.037Get rights and content
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Highlights

  • Oxazoles derived from diet, industrial sources, and microbes activate IDO1

  • Environmental oxazoles induce tryptophan-derived metabolites to activate AhR in IECs

  • AhR activation in IECs limits CD1d-restricted production of IL-10

  • Oxazole activation of AhR in IECs results in iNKT-mediated intestinal inflammation

Summary

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.

Keywords

inflammatory bowel disease
natural killer T cell
mucosal inflammation
microbiota
microcin
oxazole
aryl hydrocarbon receptor
CD1d
intestinal epithelial cell
tryptophan
indoleamine 2,3 dioxygenase

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