The aryl hydrocarbon receptor: a rehabilitated target for therapeutic immune modulation

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.

Fig. 1 ∣. Canonical and non-canonical AHR signalling.

a, During canonical aryl hydrocarbon receptor (AHR) signalling, the inactive AHR complex containing heat shock protein 90 (HSP90), AHR-interacting protein (AIP), p23 and c-Src is bound by an agonist and translocates from the cytoplasm to the nucleus where it interacts with the AHR nuclear translocator (ARNT). The AHR–ARNT heterodimer binds to DNA sequences with xenobiotic or dioxin response elements (XREs/DREs), leading to transcription of AHR target genes. The regulatory feedback mechanisms that limit AHR activation (red) include post-transcriptional modulation of AHR expression by non-coding RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs); the ubiquitin-dependent proteasome-mediated degradation of AHR; agonist degradation by CYP1A1; ADP-ribosylation of AHR and/or co-factors by TIPARP; and competition for ARNT binding in the nucleus by hypoxia-inducible factor 1α (HIF-1α) and the AHR repressor (AHRR). b, In non-canonical AHR signalling in the cytoplasm, the agonist-activated AHR promotes the phosphorylation of c-Src targets (such as indoleamine 2,3-dioxygenase (IDO1)) or acts as an E3 ubiquitin ligase to promote the degradation of target proteins. In the nucleus, the AHR interacts with other transcription factors such as nuclear factor-κB (NF-κB) to regulate transcription. AHR–ARNT also associates with the oestrogen receptor (ESR) and p300 to activate XRE/DRE-independent target genes. In addition, shear or oxidative stress induce ligand-independent AHR activation and induction of CYP1A1. CUL4B, cullin 4B ubiquitin ligase complex; P, phosphorylation; SOCS2, suppressor of cytokine signalling 2; TIPARP, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase; Ub, ubiquitylation.

Fig. 2 ∣. The AHR regulates innate and adaptative immunity.

a, In dendritic cells (DCs), agonist activation of the aryl hydrocarbon receptor (AHR) reduces the expression of MHC class II antigen presentation molecules and CD80/CD86, reduces the production of pro-inflammatory cytokines IL-6, IL-12 and TNF, and increases retinoic acid production. Additionally, the AHR and AHR nuclear translocator (ARNT) induce expression of IDO1/IDO2, to convert tryptophan (Trp) into kynurenine (Kyn), and increase production of TGFβ and IL-27, thereby indirectly impacting T cell differentiation. Activation of the AHR in DCs induces T regulatory cell (T_reg cell) and type 1 regulatory T cells (Tr1 cells) but suppresses T helper 17 cell (T_H17 cell) differentiation. b, The AHR directly modulates T cell polarization, controlling the balance between T_reg cells and effector T_H17 cells. TGFβ and the AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induce differentiation of T_reg cells. Activated AHR impairs signal transducer and activator of transcription 1 (STAT1) activation and induces SMAD1, which enhances expression of Foxp3. AHR expression also increases expression of T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) in T_reg cells. IL-27 induces the differentiation of Tr1 cells and STAT3-driven AHR expression. The AHR cooperates with c-MAF to induce expression of IL-10, IL-21 and CD39. IL-21 stabilizes Tr1 cells, whereas IL-10 and CD39 lead to immunosuppression. For example, conversion of extracellular ATP (eATP) into adenosine by CD39 and CD73 contributes to immunosuppressive effects. Hypoxia-inducible factor 1α (HIF-1α) inhibits the AHR in Tr1 cells. In T_H17 cells, IL-6 and IL-21 induce activation of STAT3, which drives AHR expression. AHR expression induces differentiation of T_H17 cells by driving Aiolos expression and inhibiting STAT1 and STAT5 activation; it also promotes RORγt-dependent IL-22 production. AHR expression promotes the conversion of T_H17 cells into Tr1 cells. AIP, AHR-interacting protein; HSP90, heat shock protein 90; IDO, indoleamine 2,3-dioxygenase; XRE/DRE, xenobiotic and dioxin response element.

Fig. 3 ∣. Probiotics impact AHR signalling.

In mouse studies, oral delivery of engineered or natural probiotics induces tryptophan (Trp) metabolism and, consequently, generates aryl hydrocarbon receptor (AHR) ligands in the intestine. In intestinal epithelial cells, AHR activation promotes homeostasis by blocking nuclear factor-κB (NF-κB) activation, stimulating signal transducer and activator of transcription 3 (STAT3) phosphorylation and increasing expression of IL-22 and CYP1A1. In T cells, the activated AHR leads to generation of CD4⁺CD8αα⁺ double-positive cells and induces tolerogenic function. In central nervous system (CNS)-resident astrocytes and microglial cells, the AHR is activated by Trp metabolites to limit neuroinflammation. AIP, AHR-interacting protein; HSP90, heat shock protein 90; P, phosphorylation.

Fig. 4 ∣. Nanoparticle-loaded agents for AHR modulation.

a, Nanoparticles can be loaded with aryl hydrocarbon receptor (AHR) ligands or antigens to modulate antigen-specific immune responses in preclinical models. For example, nanoparticles loaded with 6′-bromoindirubin-3′-acetoxime, a synthetic compound that inhibits the kinase glycogen synthase kinase 3 (GSK3), reduced indoleamine 2,3-dioxygenase (IDO1) expression and limited kynurenine (Kyn)-driven AHR activation to enhance tumour cell killing by CD4⁺ T cells; nanoparticles that co-deliver AHR ligands and antigens influenced dendritic cell (DC) and T cell polarization to boost regulatory responses; and nanoparticles loaded with the AHR agonist indole acetic acid (IAA) promoted intestinal barrier integrity. b, Plant-derived exosome-like nanoparticles (PDENs) from Portulaca oleracea enhanced growth of the Lactobacillus reuteri microbiota, inducing indole metabolism and activating the AHR, which led to decreased pro-inflammatory cytokines during colitis. MS, multiple sclerosis; T1D, type 1 diabetes; T_reg cell, regulatory T cell; Tr1 cell, type 1 regulatory T cell.