The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

Abstract

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease-especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

Keywords: aryl hydrocarbon receptor (AHR); aryl hydrocarbon response element (AHRE); single nucleotide polymorphisms (SNPs); tryptophan (TRP).

Figure 1

AHR Mechanism of Action. Prior to ligand binding, AHR is bound by cochaperones Hsp90 and XAP, which maintain its localization in the cytoplasm. After ligand binding, it is released from its cochaperones and is transported into the nucleus, where it heterodimerizes with ARNT and binds to DNA—often binding to AHREs (5′-CACGC-3′)—and regulates gene expression. AHRR is a prototypic AHR target gene and the encoded protein is a negative regulator of AHR. The arrows show the sequence of events that includes interaction, transport, DNA binding, gene expression and RNA translation. The T bar demonstrates that AHRR negatively regulates the AHR-ARNT interaction. AHR: aryl hydrocarbon receptor; AHRE: AHR response element; AHRR: AHR repressor; ARNT: aryl hydrocarbon receptor nuclear translocator; Hsp90: heat shock protein 90; XAP: X-associated protein 2.

Figure 2

Tryptophan Metabolism Pathway. Tryptophan is metabolized by two main pathways: the serotonin pathway (~1% of tryptophan metabolism) and the kynurenine pathway (~95% of tryptophan metabolism). The rate limiting enzymes IDO1/2 can be induced with pro-inflammatory cytokines, resulting in the production of more kynurenine, which is an agonist for AHR. AHR can also regulate the expression of IDO1/2, TDO2, KYNU, and KMO. The black arrows indicate enzymatic reactions, the red arrows indicate positive (+) regulation and the blue arrows indicate negative (−) regulation. DDC: dopa decarboxylase; HAAO: 3-hydroxyanthranilate 3,4-dioxygenase; IDO: indoleamine 2,3-dioxygenase; KATs: kynurenine amino transferases; KMO: Kynurenine 3-Monooxygenase; KYNU: Kynureninase; MAOA/B: monoamine oxidase A/B; TDO2: tryptophan 2,3-dioxygenase; TPH1/2: tryptophan hydroxylase.