Aryl hydrocarbon receptor: current perspectives on key signaling partners and immunoregulatory role in inflammatory diseases

Abstract

The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to a wide range of small molecules originating from the environment, our diets, host microbiomes, and internal metabolic processes. Increasing evidence highlights AhR's role as a critical regulator of numerous biological functions, such as cellular differentiation, immune response, metabolism, and even tumor formation. Typically located in the cytoplasm, AhR moves to the nucleus upon activation by an agonist where it partners with either the aryl hydrocarbon receptor nuclear translocator (ARNT) or hypoxia-inducible factor 1β (HIF-1β). This complex then interacts with xenobiotic response elements (XREs) to control the expression of key genes. AhR is notably present in various crucial immune cells, and recent research underscores its significant impact on both innate and adaptive immunity. This review delves into the latest insights on AhR's structure, activating ligands, and its multifaceted roles. We explore the sophisticated molecular pathways through which AhR influences immune and lymphoid cells, emphasizing its emerging importance in managing inflammatory diseases. Furthermore, we discuss the exciting potential of developing targeted therapies that modulate AhR activity, opening new avenues for medical intervention in immune-related conditions.

Keywords: AhR; Aryl hydrocarbon receptor; immune regulation; inflammatory diseases; signaling pathways.

Figure 1

Schematic representation of the human AhR structure: The three different domains include the N-terminal bHLH domain, Per-ARNT-Sim (PAS) domains (PAS A and PAS B), and a C-terminal transactivation domain. The numbers in red represent the amino acids spanning each domain. This illustration was created with Biorender.com.

Figure 2

The activation pathways of AhR: In the genomic (canonical) pathway, an inactive form of the AhR is cytoplasmic and complexed with HSP90, AIP and SRC. Upon ligand binding, the AhR complex translocates to the nucleus, where the AhR forms a complex with ARNT and binds to xenobiotic response element, inducing AhR-target gene expression. The AhR non-canonical pathway also induce transcription of genes involved in inflammation, immune response and/or development. AHRR competes with the AhR for binding with ARNT and forms the inactive heterodimer AHRR-ARNT. The dissociation of the AhR transcriptional complex leads to translocation of the AhR to the cytoplasm, where it is degraded via the proteasomal pathway. AhR, aryl hydrocarbon receptor; AHRR, AhR repressor; ARNT, AhR nuclear translocator; AIP, AhR-interacting protein and Ub, ubiquitin. This illustration was created with Biorender.com.

Figure 3

Aryl hydrocarbon receptor (AhR) regulates gene expression in response to environmental and endogenous stimuli. The activation of the AhR can modulate several signaling pathways, each contributing to diverse biological functions such as HIF-1α, NF-κB, Nrf2, MAPK, EGFR, JAK/STAT and ubiquitin-proteasome (Ub) pathways. This illustration was created with Biorender.com.

Figure 4

The interplay between AhR and Nrf2. Ligand-activation of AhR results in its nuclear translocation, where it dimerizes with ARNT and induces the transcription of xenobiotic-responsive element (XRE)-regulated phase I and II detoxifying enzymes, and Nrf2. Phase I detoxifying enzymes convert AhR ligands into reactive metabolites which again can lead to the formation of reactive oxygen species (ROS). ROS can trigger the dissociation of the cytosolic Nrf2-KEAP1 complex resulting in the nuclear translocation of Nrf2. This results in the expression of antioxidative response elements (ARE)-controlled phase II detoxifying enzymes, as well as the AhR. Furthermore, there is some overlap between the AhR and Nrf2 target gene batteries; for example, both routes regulate the expression of the genes NQO1 and SOD1. This illustration was created with Biorender.com.

Figure 5

The interplay between AhR and MAPKs. AhR activation has bi-directional crosstalk between MAPKs and AhR pathways. It enhances the expression and phosphorylation of ERK1/2, P38 and MKK4/7. AhR ligands can activate one or more MAPKs, depending on the ligands and different cells leading to target gene transactivation such as enhance production of CYP1A1, CYP1A2, CYP1B1, JUN and COX-2. This illustration was created with Biorender.com.

Figure 6

The ligand-activated AhR activates EGFR and downstream signaling. The ligand-driven dissociation of the AhR complex leads to the release of c-Src, which can (I) directly activate the epidermal growth factor receptor (EGFR) by phosphorylating its intracellular domain, and (II) sequentially activate protein kinase C (PKC) and sheddases resulting in ectodomain shedding of cell surface-bound EGFR ligands. In addition, nuclear AhR transactivates genes encoding EGFR ligands, such as amphiregulin (AREG) and epiregulin (EREG) (III). Independently from its mode of activation, i.e. ligand-binding or intracellular phosphorylation, the EGFR monomer changes its conformation from tethered to untethered and forms a hetero- or homodimer leading to activation of downstream signaling pathways like MAPK or JAK/STAT. This illustration was created with Biorender.com.

Figure 7

The ligand-activated AhR interacts with JAK/STAT pathway. (A) AhR ligand bound to AhR receptor, will translocate AhR into the nucleus and forms a heterodimer to drive transcription of AhR target genes such as CYP enzymes and regulates the expression of different JAK/STAT-stimulating cytokines including IL-2, IL-10, IL-21, IL-22. In addition, both AhR ligand called 3-methylcholanthrene and β-naphthoflavone led to the AhR-dependent suppression of STAT 5 and STAT3 activation expression, respectively. (B) Cytokines and growth factors bind to their receptors, leading to receptor dimerization and recruitment of related JAKs. JAK activation leads to phosphorylation of the receptors and formation of docking sites for STAT. Then, STATs dissociate from the receptor to form homodimers or heterodimers. These STAT dimers enter the nucleus, bind to DNA, and regulate transcription to release IDO1 in human chronic lymphocytic leukemia cells. Furthermore, tryptophan is oxidized by IDO1 to N-formylkynurenine, which is further converted by aryl formamidase into KYN. KYN and its metabolites act as AhR agonists that induce immunosuppressive Tregs and simulate TCDD effects. This illustration was created with Biorender.com.

Figure 8

AhR-activation orchestrates both positive and negative regulatory effects on immune cells. AhR-mediated response to exogenous or endogenous ligands influences the activity of adaptive and innate immune responses. AhR signaling affects the polarization of macrophages, suppressing the function of NK cells. Moreover, AhR signaling inhibits the expression of IL-5, IL-13 and enhances the production of IL-22 by ILC3. AhR signaling also effects T cell and B cell differentiation. AhR activation impairs regulation of myeloid derived suppressor cells (MDSCs) and influences the activation of dendritic cell functions. These effects of AhR ultimately imbalance the M1/M2 polarization and Th17/Treg balance. This illustration was created with Biorender.com.