Feedback control of AHR signalling regulates intestinal immunity
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2017-02-09
Date Acceptance
2016-12-22
Citation
Nature, 2017, 542 (7640), pp.242-245
ISSN
0028-0836
Publisher
Nature Publishing Group
Start Page
242
End Page
245
Journal / Book Title
Nature
Volume
542
Issue
7640
Copyright Statement
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000393737500043&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
ARYL-HYDROCARBON RECEPTOR
AGONISTS
GUT
INTERLEUKIN-22
ACTIVATION
DEFENSE
SYSTEM
MOUSE
CELLS
Publication Status
Published
Date Publish Online
2017-02-01