The Aryl Hydrocarbon Receptor: Connecting Immunity to the Microenvironment

Abstract

The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and transcription factor activated through cognate ligand binding. It is an important factor in immunity and tissue homeostasis, and structurally diverse compounds from the environment, diet, microbiome, and host metabolism can induce AhR activity. Emerging evidence suggests that AhR is a key sensor allowing immune cells to adapt to environmental conditions and changes in AhR activity have been associated with autoimmune disorders and cancer. Furthermore, AhR agonists or antagonists can impact immune disease outcomes identifying AhR as a potentially actionable target for immunotherapy. In this review, we describe known ligands stimulating AhR activity, downstream proinflammatory and suppressive mechanisms potentiated by AhR, and how this understanding is being applied to immunopathology to help control disease outcomes.

Figure 1:. The AhR transcriptional circuit in mammalian cells.

The inactive form of the aryl hydrocarbon receptor (AhR) is present in the cytosol as a complex with the chaperone proteins HSP90, P23, and AIP. Multiple AhR ligands from the gut microbiome, host metabolism, diet, and environment induce a conformational change in AhR exposing the nuclear localization signal initiating nuclear shuttling. Recently an additional mechanism was shown to activate AhR via DNA exposed on apoptotic cells or apoptotic microparticles dependent on Toll-Like Receptor 9 (TLR9) [4]. Once in the nucleus, AhR forms a dimer with the AhR nuclear translocator (ARNT) binding to the XRE/DRE sequence motif 5’-GCGTG-3’. This induces expression of genes involved in AhR ligand metabolism and immune regulation. Furthermore, AhR drives expression of AhR repressor (AHRR) disrupting the AhR/ARNT heterodimer and suppressing its transcriptional activity. In addition, AhR functions as a CUL4B-based E3 ubiquitin ligase complex driving selective protein degradation. Regulation of AhR pathway is controlled through nuclear export and subsequent degradation of AhR via the ubiquitin-proteasome pathway.

Figure 2:. Biosynthesis of AhR ligands through the tryptophan metabolism.

Tryptophan is metabolized into a variety of AhR ligands affecting immunity, maintenance of epithelial barrier function and microbiome diversity. Host metabolites with AhR agonistic activity are primarily derived from tryptophan metabolism via the kynurenine pathway, with additional ligands produced by UV-exposure and oxidative reactions. In the GI tract multiple bacterial species (e.g. C. sporogenes, L. reuteri, E.coli, A. pascens) present in the microbiota metabolize tryptophan to products with potent AhR agonistic properties. Moreover, cruciferous vegetables contain the tryptophan metabolite glucosinolate, which undergoes a hydrolysis reaction forming the AhR protoagonist I3C. In the stomach I3C is metabolized via an acid-condensation reaction into the AhR ligands DIM, ICZ, and LTr1.