Feedback control of AHR signalling regulates intestinal immunity

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 (Lead / Corresponding author)

    Research output: Contribution to journalLetter

    121 Citations (Scopus)
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    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.

    Original languageEnglish
    Pages (from-to)242-245
    Number of pages4
    JournalNature
    Volume542
    Issue number7640
    Early online date1 Feb 2017
    DOIs
    Publication statusPublished - 9 Feb 2017

    Keywords

    • Acute inflammation
    • Mucosal immunology

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  • Cite this

    Schiering, C., Wincent, E., Metidji, A., Iseppon, A., Li, Y., Potocnik, A. J., Omenetti, S., Henderson, C. J., Wolf, C. R., Nebert, D. W., & Stockinger, B. (2017). Feedback control of AHR signalling regulates intestinal immunity. Nature, 542(7640), 242-245. https://doi.org/10.1038/nature21080