The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease

Abstract

The environment, diet, microbiota and body’s metabolism shape complex biological processes in health and disease. However, our understanding of the molecular pathways involved in these processes is still limited. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that integrates environmental, dietary, microbial and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner. In this Review, we summarize our current knowledge of AHR and the transcriptional programmes it controls in the immune system. Finally, we discuss the role of AHR in autoimmune and neoplastic diseases of the central nervous system, with a special focus on the gut immune system, the gut–brain axis and the therapeutic potential of targeting AHR in neurological disorders.

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Fig. 1: AHR signalling.
Fig. 2: AHR in antigen-presenting cells and T cells.
Fig. 3: AHR in intestinal epithelial cells, intraepithelial lymphocytes and innate lymphoid cells.
Fig. 4: AHR in central nervous system-resident cells.
Fig. 5: AHR as a therapeutic target.

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Acknowledgements

This work was supported by grants NS102807, NS087867, ES02530, AI126880 and AI093903 from the US National Institutes of Health, RSG-14-198-01-LIB from the American Cancer Society, RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society and PA-1604-08459 from the International Progressive MS Alliance. The authors thank all members of the Quintana laboratory for helpful advice and discussions.

Author contributions

Both V.R. and F.J.Q. researched data and reviewed and edited the manuscript. V.R. wrote the manuscript.

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Nature Reviews Immunology thanks M. Colonna and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Francisco J. Quintana.

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Competing interests

F.J.Q. is a founder of AnTolRx, a company exploring the targeting of aryl hydrocarbon receptor (AHR) with nanoparticles for the treatment of inflammatory conditions. He is also a scientific adviser for Kyn Therapeutics, a company exploring targeting AHR for cancer therapy.

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Glossary

Mediator complex

An evolutionarily conserved multisubunit protein complex controlling the activities of RNA polymerase II, which transcribes all protein-coding genes in eukaryotes. Mediator serves as a functional bridge between specific transcription factors, DNA-bound transcriptional activators or repressors and the transcriptional machinery required for the initiation of transcription by the basal transcriptional machinery (including RNA polymerase II and general transcription factors).

SWI/SNF chromatin remodelling complex

(Switching-defective/sucrose non-fermenting chromatin remodelling complex). An ATP-dependent chromatin remodelling protein complex that was first identified in yeast. Related complexes exist in mammals (where they are known as BAF) and are involved in the chromatin remodelling of various genes.

Kynurenine pathway

A metabolic pathway in which the essential amino acid tryptophan is metabolized to the cofactor NAD+ over several enzymatic steps. The first reaction in this process, mediated by the enzymes indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 or tryptophan 2,3-dioxygenase (TDO), leads to the generation of kynurenine. Kynurenine and some of its metabolites act as aryl hydrocarbon receptor (AHR) ligands and exert important functions in the immune system in inflammatory, infectious and neoplastic disorders.

T regulatory type 1 cells

(TR1 cells). A population of regulatory T cells that arises in the periphery after an encounter with antigen in the presence of IL-27 alone or in combination with transforming growth factor-β (TGFβ) and that regulates immune responses through the secretion of IL-10 and additional mechanisms. TR1 cells suppress T cell responses, downregulate the expression of co-stimulatory molecules and pro-inflammatory cytokines by antigen-presenting cells and favour the production of IgD, IgA and IgG by B cells.

Intraepithelial lymphocytes

(IELs). A T cell population found within the epithelial layer of mammalian mucosal linings. This population consists of specialized subsets of cells, such as particular T cell receptor (TCR) γδ+ T cell subsets and TCRαβ+CD8αα+ T cells.

Innate lymphoid cells

(ILCs). A population of innate immune cells that are lymphoid in morphology and developmental origin but lack properties of adaptive B cells and T cells such as recombined antigen-specific receptors. They function in the regulation of immunity, tissue homeostasis and inflammation in response to cytokine stimulation.

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Rothhammer, V., Quintana, F.J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 19, 184–197 (2019). https://doi.org/10.1038/s41577-019-0125-8

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