Feedback control of AHR signalling regulates intestinal immunity

• Published in: Nature (London) Vol. 542; no. 7640; pp. 242 - 245
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-02-2017; Nature Publishing Group
• Subjects: 631/250/256/2516; 631/250/347; Animals; Cellular signal transduction; Citrobacter rodentium - immunology; Colon - cytology; Colon - immunology; Colon - metabolism; Colon - microbiology; Cytochrome P-450 CYP1A1 - metabolism; Diet; Enzymes; Feedback, Physiological; Female; Health aspects; Humanities and Social Sciences; Immune system; Immunity (Disease); Immunity, Innate; Infections; Intestinal Mucosa - metabolism; Intestines - cytology; Intestines - immunology; Intestines - microbiology; letter; Ligands; Male; Medicin och hälsovetenskap; Metabolism; Metabolites; Mice; multidisciplinary; Observations; Pathogens; Pathology; Physiological aspects; Receptors, Aryl Hydrocarbon - metabolism; Rodents; Science; Signal Transduction; Th17 Cells - immunology; Xenobiotics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature21080

Cytochrome P4501 enzymes have a role in the regulation of aryl hydrocarbon receptor ligand levels in the gut, affecting innate lymphoid and T
H
17 cell responses.
Cytochrome P4501 regulates AHR ligands
The aryl hydrocarbon receptor (AHR) has an important role in the maintenance of homeostasis at mucosal surfaces. When activated by foreign material or metabolites, it induces cytochrome P4501 enzymes, resulting in detoxification. Here, Chris Schiering
et al
. report a role for cytochrome P4501 enzymes in the regulation of AHR ligand levels in the gut, affecting the responses of type 3 innate lymphoid cells and T helper 17 cells.
The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors
1
,
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 detoxification
5
. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling
6
, 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.