Feedback control of AHR signalling regulates intestinal immunity View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-02-01

AUTHORS

Chris Schiering, Emma Wincent, Amina Metidji, Andrea Iseppon, Ying Li, Alexandre J. Potocnik, Sara Omenetti, Colin J. Henderson, C. Roland Wolf, Daniel W. Nebert, Brigitta Stockinger

ABSTRACT

The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors, and it is important for maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling, but it remains unclear whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 in mice depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of AHR-dependent type 3 innate lymphoid cells and T helper 17 cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasize the importance of feedback control in modulating AHR pathway activation. More... »

PAGES

242

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature21080

DOI

http://dx.doi.org/10.1038/nature21080

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1083401659

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28146477


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