The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors1,2,3,4, 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 detoxification5. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling6, 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.
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This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK, The UK Medical Research Council and the Wellcome Trust. We would like to acknowledge the Biological Research Facility at the Francis Crick Institute for expert breeding and maintenance of our mouse strains, the Histopathology Facility for help with sections and staining and the Flow Cytometry Facility. We thank G. Frankel (Imperial College) for the gift of antiserum to C. rodentium and Genentech, South San Francisco, California, for providing anti-IL-22 and IL-22–Fc. The study was supported by a Wellcome Advanced Investigator Grant (B.S.) and a Sir Henry Wellcome Fellowship and the Fondation Acteria (C.S.). C.H. and C.R.W. are funded by Cancer Research UK Programme Grant C4639/A10822. E.W. is funded by the Swedish Research Council FORMAS and D.N. by National Institute of Environmental Health Sciences, NIH grant R01 ES014403.
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Activation of AhR with nuclear IKKα regulates cancer stem-like properties in the occurrence of radioresistance
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