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

    94 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

    Fingerprint

    Aryl Hydrocarbon Receptors
    Immunity
    Ligands
    Cytochromes
    Epithelial Cells
    Th17 Cells
    Microbiota
    Xenobiotics
    Enzymes
    Tryptophan
    Homeostasis

    Keywords

    • Acute inflammation
    • Mucosal immunology

    Cite this

    Schiering, C., Wincent, E., Metidji, A., Iseppon, A., Li, Y., Potocnik, A. J., ... Stockinger, B. (2017). Feedback control of AHR signalling regulates intestinal immunity. Nature, 542(7640), 242-245. https://doi.org/10.1038/nature21080
    Schiering, Chris ; Wincent, Emma ; Metidji, Amina ; Iseppon, Andrea ; Li, Ying ; Potocnik, Alexandre J. ; Omenetti, Sara ; Henderson, Colin J. ; Wolf, C. Roland ; Nebert, Daniel W. ; Stockinger, Brigitta. / Feedback control of AHR signalling regulates intestinal immunity. In: Nature. 2017 ; Vol. 542, No. 7640. pp. 242-245.
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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.",
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    note = "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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    Schiering, C, Wincent, E, Metidji, A, Iseppon, A, Li, Y, Potocnik, AJ, Omenetti, S, Henderson, CJ, Wolf, CR, Nebert, DW & Stockinger, B 2017, 'Feedback control of AHR signalling regulates intestinal immunity', Nature, vol. 542, no. 7640, pp. 242-245. https://doi.org/10.1038/nature21080

    Feedback control of AHR signalling regulates intestinal immunity. / Schiering, Chris; Wincent, Emma; Metidji, Amina; Iseppon, Andrea; Li, Ying; Potocnik, Alexandre J.; Omenetti, Sara; Henderson, Colin J.; Wolf, C. Roland; Nebert, Daniel W.; Stockinger, Brigitta (Lead / Corresponding author).

    In: Nature, Vol. 542, No. 7640, 09.02.2017, p. 242-245.

    Research output: Contribution to journalLetter

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    T1 - Feedback control of AHR signalling regulates intestinal immunity

    AU - Schiering, Chris

    AU - Wincent, Emma

    AU - Metidji, Amina

    AU - Iseppon, Andrea

    AU - Li, Ying

    AU - Potocnik, Alexandre J.

    AU - Omenetti, Sara

    AU - Henderson, Colin J.

    AU - Wolf, C. Roland

    AU - Nebert, Daniel W.

    AU - Stockinger, Brigitta

    N1 - 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.

    PY - 2017/2/9

    Y1 - 2017/2/9

    N2 - 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.

    AB - 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.

    KW - Acute inflammation

    KW - Mucosal immunology

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    Schiering C, Wincent E, Metidji A, Iseppon A, Li Y, Potocnik AJ et al. Feedback control of AHR signalling regulates intestinal immunity. Nature. 2017 Feb 9;542(7640):242-245. https://doi.org/10.1038/nature21080