Through systematic deletion of AhR

Through systematic CDK4 inhibitor of AhR in specific cell types, Di Meglio et al. (2014) revealed that AhR in keratinocytes and fibroblasts are key to the exacerbated psoriatic phenotype induced by IMQ in AhR-deficient mice. This emphasizes the crosstalk between keratinocytes and the immune system to regulate barrier physiology or pathophysiology. Keratinocytes also release factors that increase the innervation of peripheral sensory neurons that in turn can invoke pruritus and further recruitment of inflammatory infiltrates (Hidaka et al., 2017). Indeed, epidermal hyperinnervation of peripheral sensory neurons was recently demonstrated using a constitutively active AhR, which promotes Artn expression, encoding for artemin (Hidaka et al., 2017). Application of FICZ did not induce artemin expression, nor did FICZ exposure lead to the proinflammatory response observed in constitutively active AhR mice or mice chronically exposed to the environmental toxin 7,12-dimethylbenz[a]anthracene, which is a main constituent of diesel exhaust particles, and mice exposed to 7,12-dimethylbenz[a]anthracene largely recapitulate the pathobiology of constitutively active AhR mice (Hidaka et al., 2017). Activation of AhR has previously been considered a liability target for potential treatments because of the toxicological effects associated with dioxin exposure, which has long been attributed to their persistent and bioaccumulative properties (Bradshaw and Bell, 2009). However, it now appears that AhR activation per se need not lead to toxic effects. Several marketed drugs (e.g., leflunomide, prednisolone, omeprazole, and others) have been shown to activate the AhR pathway, although AhR activation is not considered their primary mechanism of action (Hu et al., 2007). Nonetheless, these compounds are not associated with dioxin-related adverse events. Thus, although endogenous ligands, some marketed compounds, and chronic pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin share AhR as a target, their effects differ (Farmahin et al., 2016). It will be critical to understand how the chronicity of ligand signaling or differential binding leads to alternative AhR signaling mechanisms and distinct downstream biology.
Materials and Methods
Conflict of Interest
Acknowledgments
Author Contributions
Introduction The aryl hydrocarbon receptor (AHR) has historically been studied for its ability to mediate the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and to regulate the expression of the cytochrome P450 genes, CYP1A1 and CYP1B1. TCDD causes numerous toxic effects in laboratory animals, including a wasting syndrome characterized by altered energy metabolism, body weight loss and death; however, the mechanisms remain unclear [1]. AHR also regulates many biological pathways in the absence of exogenous ligands, including development, cell cycle and the immune response [2,3]. Many of these biological effects are due to the transient activation of AHR by endogenous and/or dietary ligands [4]. However, an important aspect of AHR signaling that is not well understood, and relevant for both its toxic and biological functions, is how AHR activity is controlled. This review focuses on recent findings regarding the role of the AHR target gene, TCDD-inducible poly-ADP-ribose polymerase (TIPARP) and ADP-ribosylation in regulating AHR signaling and TCDD-dependent toxicity.
The aryl hydrocarbon receptor mechanism of action The AHR is a member of the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) family, a class of transcription factors that respond to extracellular signals and environmental stresses to alter cell function [5]. The AHR is best known for its ability to bind and mediate the toxic effects of halogenated and polycyclic aromatic hydrocarbons, but it also binds numerous non-toxic dietary, endogenous and gut microbiome derived ligands [6]. The molecular mechanisms of AHR action are diverse and many outcomes are context dependent (reviewed in [7]). The canonical AHR pathway begins with ligand binding to the cytosolic chaperone-bound form of AHR, followed by its nuclear translocation and heterodimerization with the AHR nuclear translocator (ARNT). The AHR:ARNT heterodimer binds to AHR response elements (AHREs) located in proximal regulatory regions, distal enhancers and intronic sequences in an a battery of AHR target genes that are involved in numerous cellular pathways [8,9]. Well-established AHR target genes include CYP1A1, CYP1B1, and AHR repressor (AHRR) and TIPARP (also called PARP7/ARTD14) [10–12]. As with all transcription factors, tight regulation of AHR activity is necessary to prevent its over-activation. However, comparatively little is known about how AHR signaling is controlled. In many cases, AHR activity is attenuated by the induction of CYP1A1/CYP1B1 enzymes that metabolize and inactivate several AHR ligands. Ligand activated AHR is also proteolytic degraded by the 26s proteasome; however, the level and extent of this degradation varies among cell lines and ligands [13]. In addition, AHR is regulated through a negative feedback loop, where increased AHRR levels inhibit AHR activity through competition with ARNT and/or by tethering to the AHR-ARNT complex [12,14]. Recent studies, indicate that AHRR is a context and tissue-specific negative regulator of AHR, suggesting that there are other mechanisms controlling AHR activity [15,16].