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The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

ABSTRACT: Innate lymphoid cells (ILCs) expressing the nuclear receptor ROR?t are essential for gut immunity presumably through production of interleukin-22 (IL-22). The molecular mechanism underlying the development of ROR?t(+) ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in ROR?t(+) ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal ROR?t(+) ILCs. Without Ahr, ROR?t(+) ILCs had increased apoptosis and less production of IL-22. ROR?t interacted with Ahr and promoted Ahr binding at the Il22 locus. Upon IL-23 stimulation, Ahr-deficient ROR?t(+) ILCs had reduced IL-22 expression, consistent with downregulation of IL-23R in those cells. Ahr-deficient mice succumbed to Citrobacter rodentium infection, whereas ectopic expression of IL-22 protected animals from early mortality. Our data uncover a previously unrecognized physiological role for Ahr in promoting innate gut immunity by regulating ROR?t(+) ILCs.

SUBMITTER: Qiu J

PROVIDER: S-EPMC3268875 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

Qiu Ju J Heller Jennifer J JJ Guo Xiaohuan X Chen Zong-ming E ZM Fish Kamonwan K Fu Yang-Xin YX Zhou Liang L

Immunity 20111215 1

Innate lymphoid cells (ILCs) expressing the nuclear receptor RORγt are essential for gut immunity presumably through production of interleukin-22 (IL-22). The molecular mechanism underlying the development of RORγt(+) ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in RORγt(+) ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal RORγt(+) ILC ...[more]

PMID: 22177117

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Project description:Background/objectivesLow-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts.MethodsWe screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation.ResultsWe identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT.ConclusionsIndigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.

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The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

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The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.

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