The Aryl Hydrocarbon Receptor: A Key Bridging Molecule of External and Internal Chemical Signals

Abstract

The aryl hydrocarbon receptor (AhR) is a highly evolutionary conserved, ligand-activated transcription factor that is best known to mediate the toxicities of dioxins and dioxin-like compounds. Phenotype of AhR-null mice, together with the recent discovery of a variety of endogenous and plant-derived ligands, point to the integral roles of AhR in normal cell physiology, in addition to its roles in sensing the environmental chemicals. Here, we summarize the current knowledge about AhR signaling pathways, its ligands and AhR-mediated effects on cell specialization, host defense and detoxification. AhR-mediated health effects particularly in liver, immune, and nervous systems, as well as in tumorgenesis are discussed. Dioxin-initiated embryotoxicity and immunosuppressive effects in fish and birds are reviewed. Recent data demonstrate that AhR is a convergence point of multiple signaling pathways that inform the cell of its external and internal environments. As such, AhR pathway is a promising potential target for therapeutics targeting nervous, liver, and autoimmune diseases through AhR ligand-mediated interventions and other perturbations of AhR signaling. Additionally, using available laboratory data obtained on animal models, AhR-centered adverse outcome pathway analysis is useful in reexamining known and potential adverse outcomes of specific or mixed compounds on wildlife.

Figure 1

AhR agonists and emerging functions of AhR as a sensor. AhR is involved in metabolism and regulates genes that are involved in detoxification of classical ligands, such as TCDD and BNF. Newly defined ligands from dietary/endogenous components or bacterial products are indicated to be important in the immune system for cell differentiation and immune privilege.

Figure 2

Roles of AhR in T cell differentiation. TGFβ, together with IL2 or IL6, induces Treg or Th17 cells to produce cytokines in tolerance and immunity while TCDD or endogenous AhR ligand could induce the same effects as TGFβ on naive CD4 ⁺ T cells. On the other hand, AhR inhibitor/antagonist or AhR deficient mice display diminished impacts on T cell differentiation.

Figure 3

Roles of AhR in gut immunity. (a) With diet-derived AhR ligands, dispersed IELs between epithelial cells and ILCs in cryptopatches are the predominant immune cells that constitute the mucosal immune system. RORγt facilitates AhR binding at the IL22 promoter in ILCs, and ILCs-derived IL22 increased epithelial cell survival and production of antimicrobial peptides, thus maintaining intestinal homeostasis and resistance to infections, especially in small intestine and colon. (b) The absence of AhR reduced potential survival of both IELs and ILCs. Diminished cryptopatches resulted in increased bacterial load and epithelial cell damage, and thus recruited inflammatory cell infiltration beneath the mucosa, accompanied by induction of proinflammatory cytokines such as IFNγ, IL17, and inflammatory cell-derived IL22.

Figure 4

Physiological role of AhR in liver tissue. AhR is highly expressed in the liver and exerts important functions in the process of liver injury. Both AhR deficiency and dioxin-induced AhR activation could result in hepatic fibrosis. Dysregulation of RA metabolism contributes to hepatic fibrosis in AhR^−/− mice. Activation of AhR in alcohol-treated HSC indicates it might facilitate hepatic fibrogenesis in ALD. Enhanced fatty acid uptake through CD36 provokes fatty infiltration of the liver. Moreover, AhR might participate in AIH via regulation of several cytokines such as IL17 and IL22.

Figure 5

AhR signal transduction in function and immune regulation of immune cells. Typically, upon activation by its ligands, AhR translocates from the cytoplasm into the nucleus and exchanges its chaperones for ARNT, subsequently binds to DREs and activates transcription of downstream target genes such as Cyp1a1. However, AhR also participates into immune cell differentiation and cytokine secretion via binding with or initiating transcription of other nuclear transcription factors, such as cMaf, RORγt, and Foxp3.