Feedback control of AHR signalling regulates intestinal immunity.
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.
The Francis Crick Institute, London, UK.
Chris
C
Schiering
Swedish Toxicology Sciences Research Center, Södertälje, Sweden.
Emma
E
Wincent
The Francis Crick Institute, London, UK.
Amina
A
Metidji
The Francis Crick Institute, London, UK.
Andrea
A
Iseppon
The Francis Crick Institute, London, UK.
Ying
Y
Li
Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, UK.
Alexandre J
AJ
Potocnik
The Francis Crick Institute, London, UK.
Sara
S
Omenetti
Dundee University School of Medicine, Division of Cancer Research, Dundee, UK.
Colin J
CJ
Henderson
Dundee University School of Medicine, Division of Cancer Research, Dundee, UK.
C Roland
CR
Wolf
University of Cincinnati, Department of Environmental Health, Cincinnati, Ohio, USA.
Daniel W
DW
Nebert
The Francis Crick Institute, London, UK.
Brigitta
B
Stockinger
D000818:Animals; D044082:Citrobacter rodentium / Q000276:immunology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D008024:Ligands; D008297:Male; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology
D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1