Feedback control of AHR signalling regulates intestinal immunity.
Feedback control of AHR signalling regulates intestinal immunity.
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DOI：
10.1038/nature21080
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发表时间：
2017-02-09
期刊：
影响因子：
64.8
通讯作者：
Stockinger B
中科院分区：
文献类型：
--
作者：
Schiering C;Wincent E;Metidji A;Iseppon A;Li Y;Potocnik AJ;Omenetti S;Henderson CJ;Wolf CR;Nebert DW;Stockinger B
The aryl hydrocarbon receptor (AHR) recognises xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors and 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 appear to play an important feedback role that curtails the duration of AHR signalling, but it remains elusive whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 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 (IECs) resulted in loss of AHR-dependent type 3 innate lymphoid cells (ILC3) and T helper 17 (Th17) 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 IECs serve as gatekeepers for the supply of AHR ligands to the host and emphasise the importance of feedback control in modulating AHR pathway activation.
