Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

Karl Walter Bock

doi:10.1515/hsz-2016-0303

Article Publicly Available

Human and rodent aryl hydrocarbon receptor (AHR): from mediator of dioxin toxicity to physiologic AHR functions and therapeutic options

Karl Walter Bock

Published/Copyright: November 1, 2016

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From the journal Biological Chemistry Volume 398 Issue 4

Abstract

Metabolism of aryl hydrocarbons and toxicity of dioxins led to the discovery of the aryl hydrocarbon receptor (AHR). Tremendous advances have been made on multiplicity of AHR signaling and identification of endogenous ligands including the tryptophan metabolites FICZ and kynurenine. However, human AHR functions are still poorly understood due to marked species differences as well as cell-type- and cell context-dependent AHR functions. Observations in dioxin-poisoned individuals may provide hints to physiologic AHR functions in humans. Based on these observations three human AHR functions are discussed: (1) Chemical defence and homeostasis of endobiotics. The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals and primates expressing the Ala381 variant while affinity to indoles remains unimpaired. (2) Homeostasis of stem/progenitor cells. Dioxins dysregulate homeostasis in sebocyte stem cells. (3) Modulation of immunity. In addition to microbial defence, AHR may be involved in a ‘disease tolerance defence pathway’. Further characterization of physiologic AHR functions may lead to therapeutic options.

Keywords: control of immunity; dioxin toxicity; human Ah receptor; physiologic AHR functions; stem/progenitor cells

Introduction

The aryl hydrocarbon receptor (AHR) is a multifunctional transcription factor of the PAS (Per-Arnt-Sim) superfamily. It is the only ligand-activated member of this family (Gu et al., 2000; Okey, 2007; Fujii-Kuriyama and Kawajiri, 2010; Omiecinski et al., 2011; Tian et al., 2015). AHR was discovered by toxicologists in studies of aryl hydrocarbon metabolism and dioxin toxicity. Dioxin refers to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most environmentally persistent and potent congener of halogenated dibenzodioxins, dibenzofurans and related halogenated biphenyls. However, recent interest has shifted to physiologic functions of AHR and its control of immunity (Marshall and Kerkvliet, 2010; Quintana and Sherr, 2013; Stockinger et al., 2014). Despite decades of intensive research physiologic AHR functions in humans are not fully understood. Major difficulties are the marked species differences as well as cell type- and cell context-dependent AHR functions. Physiologic AHR functions are suggested by observations in AHR-deficient mice (Fujii-Kuriyama and Kawajiri, 2010; Marshall and Kerkvliet, 2010; Omiecinski et al., 2011; Quintana and Sherr, 2013; Tian et al., 2015) and in dioxin-poisoned individuals (Bock 2016), as well as by evolution of positive and negative feedback loops between AHR ligands and substrates of target enzymes (Quintana and Sherr, 2013; Bock, 2014). In the present review (an update of a previous communication on the rapidly developing AHR field; see Bock, 2013) three physiologic AHR functions are discussed: (1) functions in chemical defence and endobiotic homeostasis, (2) functions in stem/progenitor cell homeostasis, and (3) functions in modulation of immunity. To obtain evidence for these functions in humans, discussion is preceded by respective toxic observations in human individuals: bioactivation of aryl hydrocarbons, chloracne (the hallmark of human dioxin toxicity), and dioxin-mediated inflammatory reactions in skin and the gastrointestinal tract. Then, physiologic AHR functions are suggested. Finally, developing therapeutic options related to these functions are discussed. Necessary investigations in human cell models and clinical studies will confirm or refute the suggested functions. Hence, multidisciplinary comparison of AHR functions may strengthen and delineate the hypothesized physiologic AHR functions in humans (Table 1).

Table 1:

Examples of human AHR functions in dioxin toxicity (left), in physiology (middle) and therapeutic options (right).

Selected AHR functions
Toxicology	Physiology	Therapeutic options
Chemical defence and homeostasis of endobiotics
Bioactivation of aryl hydrocarbons	Chemical defence and homeostasis of endobiotics	–
Homeostasis of stem/progenitor cells
Dioxin-mediated chloracne	Stem/progenitor cell homeostasis	Expansion of stem/progenitor cells by AHR antagonists (StemRegenin1)
Modulation of immunity
Dioxin-mediated intestinal Inflammation	Microbial defence and microbiome-host interactions	Immunosuppression of autoimmune diseases by AHR agonists

AHR history

Rodent AHR was discovered by Alan Poland in 1976 (Poland et al., 1976). His discovery was based on important contributions of Daniel Nebert. In 1968 Daniel Nebert and Harry Gelboin described a substrate-inducible microsomal aryl hydrocarbon hydroxylase (AHH) (Nebert and Gelboin, 1968). Nebert demonstrated the simple Mendelian expression of polycyclic aromatic hydrocarbons (PAH)-induced AHH in some mouse strains including C57Bl/6 (termed responsive), and the absence of induction in other strains including DBA/2 (termed nonresponsive) (Gielen et al., 1972). Thereafter, Nebert and Poland observed that the potent dioxin TCDD was able to induce AHH in nonresponsive strains suggesting that both responsive and nonresponsive strains have the structural and functional genes necessary for AHH induction (Poland et al., 1974). In 1976, Poland using [³H]-TCDD demonstrated a small pool of high affinity sites in C57Bl/6 mice in liver cytosol and much less binding in DBA/2 mice. PAHs competed with [³H]-TCDD binding. Binding sites closely correlated with potencies of many dioxins (Poland et al., 1976). Purification of the AHR was aided by synthesis of a photoaffinity ligand 2-azido-3-([¹²⁵J]iodo-7,8-dibromodibenzo-p-dioxin (Poland et al., 1991). In 1992, Christopher Bradfield’s and Yoshiaki Fujii-Kuriyama’s groups independently identified the AHR as a ligand-activated transcription factor of the PAS family (Burbach et al., 1992; Ema et al., 1992). Human AHR cDNA was identified in 1993 (Dolwick et al., 1993). It was found to be expressed at its highest levels in placenta, lung and heart. AHR-deficient mice were viable although with reduced fecundity (Fernandez-Salguero et al., 1995; Schmidt et al., 1996; Mimura et al., 1997). Phenotypic consequences of AHR knockout in mice demonstrated a clear role of AHR in multiple normal physiologic processes including chemical and microbial defence, tissue development and the adaptation of immune biology (Gu et al., 2000; Fujii-Kuriyama and Kawajiri, 2010; Quintana and Sherr, 2013).

Genomic and nongenomic AHR signaling and AHR ligands

Ligand-independant AHR signaling operates in invertebrates (Reitzel et al., 2014) and vertebrates (Puga et al., 2009). Nervertheless, ligand-dependent genomic signaling is emphasized in the present review.

Genomic signaling

AHR resides in cytosol in complex with chaperones. In the canonical genomic signaling pathway, ligand binding triggers conformational changes, translocation to the nucleus and dissociation of the chaperone complex. In the nucleus AHR associates with its partner protein ARNT and binds to specific DNA sequences of target genes, termed XREs (xenobiotic response elements) (Gu et al., 2000). Recently, it was discovered that the AHR also associates with noncanonical partners including Klf6 involved, e.g. in cell cycle control in the mouse model (Jackson et al., 2014) and human NF-κB subunits Rel A and Rel B involved in tissue inflammation (Vogel et al., 2007; Quintana and Sherr, 2013; Vogel et al., 2014).

Nongenomic signaling

Recently, multiple nongenomic AHR signaling pathways have been identified: (i) Ca²⁺-mediated phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) activation (Matsumura, 2009), (ii) translocation of c-Src to the plasma membrane and activation of EGF receptor (Matsumura, 1994; Köhle et al., 1999; Fritsche et al., 2007) and (iii) association with E3 ubiquitin ligases leading to degradation of the estrogen receptor (Ohtake et al., 2007; Quintana and Sherr, 2013).

AHR ligands

Currently, many endo- and xenobiotics are being identified as AHR ligands including metabolites of tryptophan, of heme and eicosanoids, in addition to phytochemicals, toxins and drugs (Table 2) (Nguyen and Bradfield, 2008; Quintana and Sherr, 2013). It is currently hypothesized that there are multiple endogenous and exogenous AHR ligands contributing to AHR-dependent physiologic processes in a cell-type- and cell context-dependent manner. Interestingly, potent ligands such as 6-formylindolo[3,2-b]carbazole (FICZ) are efficiently degraded by the prototypical AHR target CYP1A1, leading to negative feedback loops and transient AHR activation, in contrast to sustained AHR activation by TCDD (Wincent et al., 2009; Smirnova et al., 2016). Negative feedback loops are also operating between the AHR ligand bilirubin and UGT1A1 (Kapitulnik, 2004; Bock and Köhle, 2010). Notably, negative feedback between ligands other than FICZ and bilirubin is possible but not always proven. Interestingly, AHR is also involved in amplification of AHR activation by positive feedback loops including AHR-mediated induction of indoleamine-2,3-dioxygenase 1 (IDO1) (Vogel et al., 2008) which generates AHR agonists such as kynurenine (Quintana and Sherr, 2013). Kynurenine is known to boost Tregs and related dendritic cells. Tryptophan-derived indoles are also involved in the host-microbiome interaction in the intestine (Quintana and Sherr, 2013; Tian et al., 2015).

Table 2:

Selected AHR ligands.

Selected AHR ligands
Endobiotic	Phytochemical	Xenobiotic
Tryptophan metabolites:	Indole-3-carbinol	Toxins:
Indole	3,3′-Diindolylmethane (DIM)	TCDD Benzo[a]pyrene
Indole-3-aldehyde	Indolo[3,2-b]carbazole (ICZ)
Kynurenine (positive feedback)
FICZ (negative feedback) ITE
Heme metabolites:		Drugs in development (antagonists):
Bilirubin		StemRegenin1 in Phase 1/2 clinical trials
Eicosanoids:		Drugs in development (agonists):
Lipoxin A		Leflunomide
		VAF347
		ITE in nanoparticles

References are given in Nguyen and Bradfield (2008); Quintana and Sherr (2013).

Notably, a number of mechanisms evolved to avoid sustained AHR activity, for example, the discussed FICZ-mediated negative feedback loop. Two other mechanisms regulate AHR activity: first, AHR is released from the nucleus to cytosol and degraded by proteasome. Second, AHR repressor competes with AHR for dimerization with the partner protein ARNT, and efficiently represses AHR target gene expression (Omiecinski et al., 2011; Quintana and Sherr, 2013).

AHR functions in chemical defence and endobiotic homeostasis

As in rodents and all vertebrates, the human AHR is involved in homeostasis of lipophilic endo- and xenobiotics including drugs. Hence, it is regulating subsets of the drug-metabolizing enzyme system (Bock, 2014).

Bioactivation of aryl hydrocarbons

For decades bioactivation of benzo[a]pyrene (BaP) to ultimate carcinogens and its implications for risk assessment has been studied (Nebert et al., 2004). Interestingly, investigations using CYP1-deficient mice suggested that in balance detoxification of BaP may be higher than bioactivation in the intestinal epithelium after oral BaP exposure (Shi et al., 2010).

Based on the studies of Ema et al. (1994), an interesting divergent AHR ligand selectivity during hominin development has been discovered. The AHR variant Val381 in modern humans leads to reduced AHR affinity to aryl hydrocarbons in comparison with Neanderthals, other hominins and primates (expressing the AHR variant Ala381) while affinity to indoles remains unimpaired (Hubbard et al., 2016). Binding of the photoaffinity ligand 2-azido-3-([¹²⁵J]iodo-7,8-dibromodibenzo-p-dioxin was much lower; CYP1A1 induction by BaP was reduced in humans carrying the Val381 variant whereas CYP1A1 induction by endogenous ligands such as indirubin and indole was unimpaired. These findings suggest that the Val381 variant determining PAH sensitivity is not critical to establish endogenous ligand sensitivity. Both Neanderthals and modern human populations were probably heavily exposed to PAHs by controlled fire (e.g. cooking fire). Nevertheless, it has been proposed that carriers of the Val381 variant acquired tolerance to bioactivation of PAHs to a degree that led to selective advantage and ultimate fixation of the variant.

Chemical defence and endobiotic homeostasis

For chemical defence the so-called drug-metabolizing enzyme system evolved including phase I enzymes (mainly CYPs), phase II conjugating enzymes (UGTs, SULTs (sulfotransferases) and GSTs (glutathione S-transferases), and phase III conjugate transporters. In addition, subsets of these enzymes appear to be coordinately regulated by transcription factors such as AHR (Bock, 2014). In addition to liver, these enzymes are mainly expressed in barrier organs such as intestine, skin and lung, but also in specialized cells such as stem/progenitor cells and macrophages (Stockinger et al., 2014). Many studies suggested tight linkage between these enzymes (Nebert et al., 2004). Tight junction is achieved, e.g. by genetic linkage between AHR and Nrf2 (Miao et al., 2005; Köhle and Bock, 2007; Shin et al., 2007; Yeager et al., 2009). Knowledge about endobiotic homeostasis is still in its infancy. Nevertheless, the feedback loop between FICZ, AHR and CYP1A1 (Wincent et al., 2009) may be important for transient AHR-dependent modulation of the cell cycle and differentiation, discussed subsequently.

AHR functions in stem/progenitor cell homeostasis

Accumulating evidence in mouse embryonic stem cells and hematopoietic system suggests that AHR is involved in regulation of stem/progenitor cells (Singh et al., 2009; Gasiewicz et al., 2014; Wang et al., 2016; Unnisa et al., 2016). Evidence for stem/progenitor cells as target of human AHR has also been obtained in studies of chloracne, the hallmark of dioxin toxicity (Ju et al., 2011; Bock, 2016).

Dioxin-mediated chloracne

Industrial accidents leading to TCDD exposure established chloracne as the hallmark of dioxin intoxication (Suskind, 1985). The oral TCDD poisoning of Victor Yushchenko in 2004 demonstrated inflammatory injury of the gastrointestinal tract and after 2 weeks the development of chloracne (Saurat et al., 2012). Concomitant accumulation of TCDD in sebum lasted for over 2 years leading to sustained activation of AHR in sebaceous gland tissue. AHR has been demonstrated to be expressed in sebocytes together with induction of Blimp1, an efficient inhibitor of c-Myc (Ikuta et al., 2010). Bipotential stem/progenitor cells have been identified and characterized in sebaceous glands, in addition to stem cells at the bulge of hair follicles and interfollicular epidermal tissue (Watt and Hogan, 2000; Arnold and Watt, 2001; Frye et al., 2003; Lo Celso et al., 2008). Contrasting roles of c-Myc and β-catenin/TCF have been demonstrated in mediating progenitor differentiation to either sebocytes or interfollicular epidermis, respectively (Lo Celso et al., 2008). In support, TCDD treatment of ex vivo sebaceous gland-rich skin culture led to atrophic sebaceous glands and increased expression of the keratinocyte differentiation marker keratin 10 (Ju et al., 2011). In conclusion, TCDD dysregulates AHR functions leading to exhaustion of stem/progenitor cells and atrophy of sebaceous glands, similar to findings in vivo (Saurat et al., 2012). These findings point to the importance of identifying AHR target cells and its cross-talking partners in mechanistic studies.

Stem/progenitor cell homeostasis

Sebocyte stem/progenitor cells The sebaceous gland matures just after birth. The main role of the gland is to generate terminally differentiated sebocytes, which produce lipids and sebum. When sebocytes disintegrate, they release these oils into the hair canal for lubrication and protection against bacterial infections. Sebaceous gland homeostasis necessitates a progenitor population that give rise to a continual flux of proliferating, differentiating, and finally, dead cells that are lost through the hair canal (Schneider and Paus, 2010).

Numerous laboratories demonstrated AHR functions in controlling the cell cycle, differentiation and apoptosis (Marlowe and Puga, 2005). Conceivably, one of the most sensitive targets of these AHR functions are stem/progenitor cells in which self-renewal and differentiation has to be balanced (Watt and Hogan, 2000). Low level AHR activity may be required for cell cycling (Ma and Whitlock, 1996). This effect guarantees stem cell self-renewal. Higher level AHR activation is known to lead to cell cycle arrest at the G₁/G₀ phase (Mitchell and Elferink, 2009). The latter effect may be required for cell differentiation. AHR is particularly suited for this purpose as it is effective in short-term cycle arrest and expression of proteins required for cell-type specific differentiation. In addition, as ligand-activated transcription factor it is able to respond to a variety of cues at the stem cell niche.

Liver stem cells Using liver stem cell-like rat WB-F344 cells TCDD-mediated release of these cells from cell to cell contact inhibition has been demonstrated (Münzel et al., 1996; Dietrich et al., 2002). Similar to the skin, there is evidence for multiple liver stem cells. The complexity of AHR actions in hepatic stem/progenitor cells has been discussed (Vondracek and Machala, 2016), but is beyond the scope of the present commentary.

Therapeutic stem/progenitor cell expansion by AHR antagonists (StemRegenin1)

The role of AHR in stem cell homeostasis stimulated research to expand pluripotent stem cells from umbilical cord blood. Treatment of human cord blood-derived hematopoietic stem cells with the AHR antagonist StemRegenin1 (SR1) was successful (Boitano et al., 2010). Phase I/II trial of expanded stem cells enhanced hematopoietic recovery after myeloablative conditioning (Wagner et al., 2016).

Similarly, SR1 may be useful to augment platelet production in vitro (Strassel et al., 2016). Platelets are produced by bone marrow megakaryocytes which themselves originate from hematopoietic stem/progenitor cells. Co-culture of peripheral blood CD34⁺ cells and bone marrow-derived mesenchymal stromal cells with SR1 led to repression of AHR function and enrichment of CD34⁺ megakaryocyte precursors (Strassel et al., 2016).

AHR functions in modulation of immunity

This topic has been discussed in excellent reviews (Esser et al., 2009, Marshall and Kerkvliet, 2010; Quintana and Sherr, 2013; Stockinger et al., 2014). Therefore, dioxin-mediated inflammation, microbial defence and microbiome-host interactions, as well as therapeutic options are discussed only briefly.

Dioxin-mediated tissue inflammation

Inflammation is known as a localized protective reaction of tissues to irritation, injury or infection in which the immune system plays a major role. Inflammatory reactions have been frequently observed in the skin and gastrointestinal tract of poisoned individuals (Saurat et al., 2012; Bock, 2016). TCDD-mediated inflammation is initiated by rapid increase of intracellular Ca²⁺, phospholipase A2 and Cox-2 activation. Cox-2 has been identified as AHR target. However, underlying mechanisms are not yet fully understood (Matsumura, 2009). Normally, acute and resolution phases of inflammation are important. For example, IL-2 and lipoxin A4 have been identified as AHR-regulated effector cytokines in acute and resolution phases, respectively (Quintana and Sherr, 2013; Stockinger et al., 2014). It is assumed that in TCDD-mediated inflammation the complex interactions of innate and adaptive immunity may be dysregulated. Interestingly, TCDD-mediated induction of a distinct subset of anti-inflammatory IL-22 producing T cells together with decreased generation of inflammatory IL-17 producing Th17 cells have been identified in humans but not in mice (Ramirez et al., 2010; Trifari and Spits, 2010; Brembilla et al., 2011).

Microbial defence and microbiome-host interaction in the intestine

Development of the neonatal immune system

The host response to infection is known to be influenced by many factors, including genetics, nutritional state, age, as well as drug and chemical exposures. Recent advances reveal that AHR modulates aspects of the innate and adaptive immune response to viral, bacterial and parasitic organisms (Lawrence and Vorderstrasse, 2013; Wheeler et al., 2014; Boule et al., 2015; Zhang et al., 2015). Interestingly, in the mouse model these studies also demonstrated differential effects of ligands such as TCDD and FICZ suggesting that AHR signaling not only depends upon the time of AHR activation but also upon the cell-type and cellular context (Wheeler et al., 2014).

Intestinal homeostasis of the lymphoid system is maintained by complex interactions between intestinal microorganisms and the gut immune system. Neonatal exposure of mice to AHR ligands is necessary to maintain intestinal epithelial function. It has been demonstrated that AHR agonists (present in the diet of newborns or secreted from microbiota) are necessary to develop and maintain intestinal lymphoid cells that are also involved in development of the intestinal mucosa via induction of the AHR target and receptor tyrosine kinase Kit (Kiss et al., 2011).

Host-microbe interactions are important in inflammatory bowel disease. Interestingly, microbial tryptophan metabolites generated by induction of IDO1 have recently been identified as human AHR-selective agonists (Zelante et al., 2013, 2014). This IDO1-AHR axis is important in the control of a ‘disease tolerance defence pathway’ (Bessede et al., 2014). Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. It is the basis for inter-kingdom signaling between enteric microflora and the immune system to promote commensalism within the gut. Interestingly, nongenomic AHR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signaling ability (Bessede et al., 2014). A notable association of gut microbiome-generated tryptophan metabolites with inflammatory bowel disease (IBD) has recently been demonstrated. Reduced production of tryptophan-generated AHR ligands has been observed in the microbiome from individuals with IBD, particularly in carriers of CARD9 risk alleles associated with IBD (Lamas et al., 2016).

Therapeutic immunosuppression of autoimmune diseases by AHR agonists

Immunosuppressive therapy by AHR agonists is viewed as a promising approach for treatment of human autoimmune disorders including Crohn’s disease and type1 diabetes (Monteleone et al., 2011, Monteleone et al., 2012, Monteleone et al., 2016). Tryptophan-derived phytochemicals including 3.3′-diindolylmethane (DIM) and indolo[3,2-b]carbazole (ICZ), generated from indole-3-carbinol formed from dietary Brassica vegetables and fruits, are known AHR agonists. In addition, the anti-inflammatory drug leflunomide has recently been identified as an AHR agonist (O’Donnell et al., 2010). Another AHR agonist, VAF347, has been demonstrated to exhibit anti-inflammatory effects in allergic lung inflammation (Platzer et al., 2009). In myeloid progenitors differentiation to monocytes and Langerhans cells was found to be impaired by VAF347 whereas granulopoiesis remained unimpaired (Platzer et al., 2009). Furthermore, retinoic acid-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells was augmented by VAF347 whereas 1,25-dihydroxyvitamin D3-induced monocytic differentiation was impaired (Ibabao et al., 2015). This model suggesting AHR-mediated balancing of differentiation bears some similarity to AHR functions in bipotential sebocyte stem/progenitor cells. Nanoparticles containing the AHR agonist 2-(1H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and the β cell antigen have been engineered to promote a tolerogenic state in spezialized cells such as insulin-producing β cells (Yeste et al., 2016).

Conclusions

AHR has been discovered in studies of aryl hydrocarbon metabolism and toxicity of dioxins. Using the mouse model enormous advances have recently been made in characterizing multiple modes of AHR signaling and identification of endogenous ligands, in particular, the tryptophan metabolites FICZ and kynurenine leading to negative and positive feedback loops, respectively. However, knowledge about human AHR functions is still scarce, particularly due to marked species differences as well as cell-type- and cell context-dependent AHR functions.

Observations in dioxin-poisoned individuals may provide hints to physiologic AHR functions in humans. Based on dioxin-mediated toxicity three human AHR functions are discussed in the present review: (1) AHR functions in chemical defence and homeostasis of endobiotics. In this context an interesting divergent ligand selectivity during hominin development has been discovered. Modern humans (in contrast to Neanderthals, other hominins and primates) express the AHR Val381 variant, leading to less sensitivity to aryl hydrocarbon bioactivation but retaining the sensitivity to endogenous indole AHR agonists generated through the IDO1-AHR axis (Hubbard et al., 2016). (2) AHR functions in homeostasis of stem/progenitor cells. Stem/progenitor cells have been suggested as AHR targets in studies of TCDD-mediated dysregulation of hematopoiesis and of sebaceous glands leading to chloracne, the hallmark of human dioxin toxicity. Roles of AHR in controlling the cell cycle and differentiation are well known. It is tempting to speculate that growth arrest by transient AHR activation may be the prerequisite for stem/progenitor cell differentiation. (3) AHR functions in modulation of immunity. Dysregulation of the immune system may lead to TCDD-mediated tissue inflammation. Studies of the underlying mechanism led to identification of AHR-induced IDO1, generating the AHR agonist kynurenine. Via this IDO1-AHR axis the AHR is involved in pathogen clearance but also in generating a process termed ‘disease tolerance defence pathway’ to prevent overreacting responses to pathogen recognition (Zelante et al., 2013, 2014; Bessede et al., 2014). Generation of the anti-inflammatory IL-22 secreting T cells in humans (IL-10 in mice) and reduction of inflammatory IL-17 have been identified in this process. Many discussed notions have to be verified by hypothesis-driven experiments. Nevertheless, observations in toxicology, physiology and therapeutic attempts may strengthen each other (Table 1). Obviously, there are other AHR functions, e.g. the role of AHR in skin tanning (Luecke et al., 2010; Jux et al., 2011), and many more will be discovered.

Accumulating knowledge of AHR functions may stimulate therapeutic options. AHR antagonists (StemRegenin1) may expand urgently needed human stem/progenitor cells. AHR agonists (DIM, leflunomide, VAF347 and ITE) may be useful to generate immune tolerance in autoimmune disease including Crohn’s disease and type1 diabetes.

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Received: 2016-10-4

Accepted: 2016-10-27

Published Online: 2016-11-1

Published in Print: 2017-4-1

Articles in the same Issue

DOI: doi.org/10.1515/hsz-2016-0303

Keywords for this article

control of immunity; dioxin toxicity; human Ah receptor; physiologic AHR functions; stem/progenitor cells