The emerging role of aryl hydrocarbon receptor in the activation and differentiation of Th17 cells

Abstract

The aryl hydrocarbon receptor (AHR) is a cytoplasmic transcription factor, which plays an essential role in the xenobiotic metabolism in a wide variety of cells. The AHR gene is evolutionarily conserved and it has a central role not only in the differentiation and maturation of many tissues, but also in the toxicological metabolism of the cell by the activation of metabolizing enzymes. Several lines of evidence support that both AHR agonists and antagonists have profound immunological effects; and recently, the AHR has been implicated in antibacterial host defense. According to recent studies, the AHR is essential for the differentiation and activation of T helper 17 (Th17) cells. It is well known that Th17 cells have a central role in the development of inflammation, which is crucial in the defense against pathogens. In addition, Th17 cells play a major role in the pathogenesis of several autoimmune diseases such as rheumatoid arthritis. Therefore, the AHR may provide connection between the environmental chemicals, the immune regulation, and autoimmunity. In the present review, we summarize the role of the AHR in the Th17 cell functions.

Overview of the domain structure, cytosolic complex and signal transduction of AHR

Although many recent investigations have implicated an immunological role of the aryl hydrocarbon receptor (AHR) [1, 2], this basic helix–loop–helix/Per–Arnt–Sim (bHLH/PAS) transcription factor was originally identified as a mediator of adaptive response to xenobiotics, including the dioxins and planar polychlorinated biphenyls (PCBs) [3, 4]. In addition to detoxification, this receptor has a role in cell proliferation, circadian rhythm, and neurogenesis as well [5]. In accordance with its diverse effects, AHR has many target genes, including: cytochrome (CYP1A1), cytochrome 1B1 (CYP1B1), UDP glucuronosyltransferase 1A1 (UGT1A1), multidrug resistance protein 1(MDR1), cytokines [interleukin 10 (IL-10), interleukin 21 (IL-21)], or receptors and transcription factors [estrogen receptor α (ERα), AHR repressor (AHRR)] and epiregulin [4–6].

The human AHR gene is about 50 kilobases long, spans through 11 exons, and is located on chromosome 7 [7] (Fig. 1a). The gene encodes a 96 kDa protein, which has several functional domains. The bHLH domain mediates the ability of the ligand-activated AHR to bind to the DNA at the xenobiotic responsive elements (XREs) region [8, 9] and facilitate protein–protein interactions, such as the interaction with heat shock protein 90 (HSP90). The Per ArntSim (PAS) domain contains two highly conserved subdomains, namely the PAS-A and PAS-B. This region is required for the dimerization with AHR nuclear translocator (ARNT) and for the interaction with the ligand, or in inactive state, for the association with the two HSP90 proteins and with the hepatitis B virus X-associated protein 2 (XAP2, also known as ARA9 or AIP) [9, 10].

Fig. 1.

a The functional domains of human AHR gene [7–10]. b The structure of unliganded AHR complex [14, 15]. c The signaling pathway of AHR upon ligand binding [16–20]

The transactivation domain (TAD) of the AHR can facilitate the binding of the transcription factors, the TATA-box-binding protein (TBP) and nuclear factor 1 (NF-1) to the promoter of the target gene [11, 12]. Finally, a Q-rich domain is located in the C-terminal region of the protein and is involved in a co-activator recruitment and transactivation [13]. The unliganded AHR complex is localized in the cytosol (Fig. 1b). The AHR interacts directly with XAP2 and two HSP90 molecules through its central region (bHLH and PAS-A for HSP90 and PAS-B region for XAP2). XAP2 also binds to HSP90 molecules through their C-terminus. The HSP90-interacting bHLH domain of AHR regulates the ligand-dependent nuclear import of the receptor, while XAP2 plays a role in the protection of ligand-free AHR against degradation, by the inhibition of receptor ubiquitination and in the regulation of cytoplasmic retention of the receptor. There are other proteins participating in this interaction, e.g., the HSP90 accessory protein prostaglandin E synthase 3 (p23), which binds to the HSP90 and stabilizes the complex and modulates the ligand responsiveness during the AHR activation process [14, 15]. Upon the ligand binding to the AHR, XAP2 is released, promoting the movement of the AHR ligand complex to the nucleus [16]. After the nuclear translocation, the HSP90 dissociates, exposing the two PAS domains which allows the binding of ARNT [17]. The binding of the AHR/ARNT complex to the XREs stimulates the transcription of AHR target genes (e.g., in CYP1A1 the consensus XRE sequence is 5′-TNGCGTG-3′ and there are multiple copies of that upstream to the promoter) [18–20] (Fig. 1c).

The AHR/ARNT signaling pathway is negatively regulated by the nuclear AHRR proteins [21, 22]. The expression of AHRR is induced by the AHR/ARNT heterodimer through binding to XREs located in the 5′-flanking region of the AHRR gene. The AHRR protein was shown to repress AHR signaling through competition with AHR for ARNT and selective interference of AHRR/ARNT with AHR/ARNT in binding to the XRE sequences [23, 24]. Therefore, AHRR and AHR constitute a regulatory loop in which the heterodimer AHR/ARNT activates the expression of the AHRR gene, while the expressed AHRR inhibits the function of the AHR. Following the activation of the target genes, the ligand-bound AHR is removed rapidly from the nucleus by its nuclear export signal (NES) and is degraded in the cytosol in an ubiquitin-proteasome-dependent way [24, 25].

It was also described that AHR may bind to other dimerization partners than ARNT, such as V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog (c-MAF) or nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). In type 1 regulatory T (Tr1) cells, the AHR/c-MAF complex induced the transactivation of the IL-10 and IL-21 promoters, which resulted in the generation of more Tr1 cells and the amelioration of the experimental autoimmune encephalomyelitis (EAE) [6, 26]. Chen and co-workers showed that AHR associates with NFκB protein in lung cancer cells. The AHR/NFκB complex then binds to the IL-6 gene and increases its expression [27].

AHR and ER

ERs have prominent effects on immune functions [28]. Recent studies show that in mice the modulation of ERα-dependent pathways decreases the sensitivity to autoimmune diseases such as lupus or arthritis and result prolonged survival [29, 30]. There are extensive data showing an intricate relationship between the AHR and ER pathways, which suggest a therapeutic potential of the AHR agonists in estrogen-related diseases [31–33]. Inhibitory crosstalk between the AHR and ER signaling was first suggested by the results of Kociba and co-workers, whose results suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment decreases both mammary and uterine tumors in female Sprague–Dawley rats [34]. Other AHR agonists, such as 3-methylcholanthrene (3-MC), have the opposite effect compared to the TCDD, as they could directly activate ERα, and may therefore represent a new class of mixed AhR/ER agonists [35].

Recent data show that TCDD-activated AHR and ARNT may interfere with the ER machinery in several ways. They compete for promoter binding, which leads to the inhibition of the transcription of ERα. In addition, they also compete for the same transcriptional partners such as NF-1 and other co-activators, or co-repressors [13, 36]. Moreover, it has been shown that TCDD activation of AHR increases the proteasomal degradation of the ERα [37, 38]. Ligand-bound AHR/ARNT complex regulates the levels of circulating 17β-estradiol (E2) by controlling the gene expression of cytochrome P450 enzymes such as CYP19 (aromatase), CYP1A1 and CYP1B1 [39]. It has been demonstrated, that upon activation of AHR/ARNT, the heterodimer associates directly with ERα in the absence of estrogen through the N-terminal A/B region of the receptor. This fully competent transcriptional unit recruits CREB-binding protein/E1A binding protein p300 protein (CBP/P300) and binds to either XRE or estrogen-response element (ERE) through the attachment functions of AHR or ERα, respectively [38, 40]. Therefore, genes that are normally controlled by estrogens might become modulated by AHR agonists and vice versa.

AHR and other transcription factors

The orphan nuclear receptor liver X receptor (LXR) has two isoforms; liver X receptor alpha (LXRα) and liver X receptor beta (LXRβ) [41, 42]. In addition to lipid metabolism [43], LXRs also play an important role in the immune response. Both isoforms of the LXRs are expressed by human CD4+ T cells. Both the production of Th1 cytokines (such as interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα) and IL-2) and Th17 cell polarization are inhibited by LXR activation [44, 45]. Importantly, AHR plays a role in the LXR-mediated inhibition of Th17 differentiation as an interacting partner of LXR. LXR-induced sterol regulatory element-binding protein 1 (Srebp-1) binds to the IL-17 promoter (to the same site as AHR), leading to the inhibition of AHR-dependent IL-17 expression [44].

AHR expression may be affected by the ligand of peroxisome proliferator-activated receptors (PPARs) [5, 46]. PPARs are mediators of both the carcinogenic effects of AHR ligands (see below) in rodents and the lipid metabolism-controlled energy homeostasis in humans [47]. Peroxisome proliferator-activated receptor alpha (PPARα), a member of this ligand-activated transcription factor nuclear receptor superfamily, binds to the PPAR response element (PPRE) sites of genes [47]. Two PPRE sites were identified within the AHR-induced target gene CYP1A1 promoter region [48]. The PPARα agonist WY-14643 (WY) was shown to induce AHR expression in high doses, and it has an additive effect with the AHR ligand 3-MC on the induction of CYP1A1 expression in Caco-2 cell line [46]. PPARγ expression is also regulated by the AHR ligand TCDD in 3T3 cells during adipogenesis [49].

TCDD inhibits the testosterone-dependent transcriptional activity (for example the prostate-specific antigen expression) and cell growth of the androgen receptor (AR)-positive LNCaP prostate cancer cell line, while it does not change the expressions of AHR, ARNT or AR [50]. AHR is constitutively active in the castration-resistant C4-2 cell line and neither the AHR nor the AR is degraded by TCDD exposure. By contrast, in the androgen-sensitive LNCaP cell line both of them are degraded. Both the phosphorylation of AR and the expression of AR-inducing genes are enhanced by TCDD in LNCaP cells [51].

Activated AHR can also interact with p65 (RelA), which is a subunit of the NFκB heterodimer, and this way it is able to inhibit NFκB activity. It is an important connection point of the effects of cytokines and AHR signalization pathway [52]. This co-operation between RelA and AHR may induce the transactivation of c-Myc in Hs578T breast cancer cells via the binding of NFκB elements, and mediating malignant transformation by environmental carcinogens [53].

Th17 cells in autoimmunity

An IL-23 dependent T cell population was observed in mice by Langrish and his colleagues, which induced the autoimmune inflammation. These T cells were generated by the effect of IL-23 [54]. The Th17 cells were called as the third determinant population of the CD4+ effector T cells, in addition to the Th1 and Th2 subpopulations [55]. These cells produce proinflammatory cytokines, such as IL-17, IL-21 and IL-22. According to recent studies, the AHR plays an essential role in the T helper 17 (Th17) cell development.

The proinflammatory effects of the Th17 cells

The IL-17 cytokine family is evolutionary conserved and can be found in mammalian and non-mammalian vertebrates as well [56]. The IL-17 cytokine family consists of IL-17A, B, C, D, E and F cytokines, the IL-17A and F are co-produced by the Th17 cells. IL-17 induces the production of other proinflammatory cytokines (e.g., IL-6, TNFα) and interleukin-1 β (IL-1β), chemokines, and matrix metalloproteinases (MMP) along with colony-stimulating factors [granulocyte–monocyte colony-stimulating factor (GM-CSF)], granulocyte colony-stimulating factor [G-CSM]). IL-17 also recruits and activates neutrophils and promotes the production of nitric oxide (NO). The elevated levels of TNFα, IL-6 and IL-17 are predictors of joint destruction in rheumatoid arthritis (RA) [57–59]. IL-22 may contribute to the pathogenesis of psoriasis by promoting the abnormal differentiation and proliferation of keratinocytes [60]. IL-22 is upregulated in the mononuclear cells, isolated from the synovial fluid of RA patients; it induces the proliferation of synovial fibroblasts and promotes osteoclastogenesis [61]. IL-21 contributes to maintain the Th17 cell phenotype via proliferation induction and promotes the natural killer (NK) cell expansion, B cell differentiation, and immunoglobulin class switch [62, 63].

The Th17 cells play a major role in the pathogenesis of several autoimmune diseases including psoriasis, RA, multiple sclerosis (MS), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and asthma. The IL-23 and IL-1β induced IL-17 production of the microglial cells contribute to the inflammation in the central nervous system (CNS) in multiple sclerosis (MS) [64]. Both IL-17 and IL-22 receptors (IL-17R and IL-22R) are expressed in the blood–brain barrier endothelial cells (BBB-ECs). The Th17 cells may transmigrate through to the BBB-ECs and promote inflammation in the CNS [65]. The increased expression of Th17 pathway associated genes, such as growth factor beta 1 (TGFB1) signal transducer and activator of transcription 3 (STAT3), IL-6, IL-23R, TNF, IL17A, IL17F, and IL21 have been observed in IBD [66, 67]. The plasma concentration of IL-17A correlated with the disease activity in SLE [68]. The elevated number of circulating Th17 cells and the increased production of Th17 cell-related cytokines (IL-17, IL-22) were also described in allergic asthma [69].

Cytokine regulation of mouse Th17 differentiation

The Th17 differentiation in mice originates from CD4+ naive T cells which constitutively express IL-12Rβ1, induced by TGFβ, IL-6 and IL-1β; furthermore, maintained and amplified by IL-23, IL-21 and TNFα (Fig. 2a) [70–73]. The TGFβ-induced Forkhead box P3 (FoxP3) expression and Treg differentiation are inhibited by IL-6; the Th17 development is supported by the combination of TGFβ and IL-6. IL-23R [70–72, 74, 75] and CCR6 [76] expression are also induced by TGFβ and IL-6. IL-23 increased the ratio of IL-17 producing T cells, but Th17 cell differentiation from naive cells was not induced by IL-23 treatment or by the combination of IL-23 and TGFβ or IL-6 [70]. The T cell receptor signaling induced IL-1R expression is upregulated by IL-6 [73]. IL-21 and IL-23R expression are also induced by IL-6 in activated CD4+ T cells. IL-21 cooperates with TGFβ to induce Th17 cell differentiation, and IL-17 and IL-22 expression. In addition, IL-23R expression is upregulated by IL-21 as well, which also induces its own expression [70, 77]. Despite the Th17-induced milieu, Th17 cells may remain sensitive to IL-12, owing to their IL-12Rβ2 expression [78].

Fig. 2.

a The differentiation and phenotypical diversity of the Th17 cells in mice [70–74, 76–80]. b The differentiation and phenotypical plasticity of the Th17 cells in human. The role of AHR in Th17 cell subpopulations was not examined in the current studies, however, like in mouse AHR has expected role in the human Th17 differentiation as well [81–91]

In 2010, two functionally distinct Th17 cell populations were described. These populations need different cytokine milieu for their differentiation (Fig. 2a). The conventional Th17 cells [Th17(β)] are differentiated upon TGFβ and IL-6 treatment, express CCL20 and CXCR6, and produce IL-9 and IL-10 in addition to IL-17A and IL-17F. The IL-23 induced Th17 cells [Th17(23)] differentiate in the presence of IL-6, IL-23 and IL-1β. These Th17(23) cells produce similar amount of IL-17F, but more IL-22 than Th17(β) cells and express CCL9 and CXCR3. Remarkably, both population express RAR-related orphan nuclear receptor gamma t (RORγt), but the Th17(23) cells express T-box protein 21 (T-bet) as well [79]. The Th17(23) cells have more important roles in autoimmunity because they become IL-17/IFNγ double producers by the presence of IL-23 [79, 80].

Cytokine regulation of human Th17 differentiation

The IL-17 producing cells originate from CD161+/CD4+ cells. CD161 is a human homolog of murine natural killer (NK) cell-associated marker (NK1.1) (Fig. 2b).The Th1/Th17 precursor cells constitutively expresses retinoic acid-related orphan receptor variant 2 (RORC2),IL-23R, IL-1RI, and CCR6 [81–83]. The human Th17 polarization from CD4+ CD45RA+ naive T cells is initiated by IL-1β and IL-6 and is inhibited by TGFβ and IL-12 [84]. The Th17 differentiation from CD4+ naive T cells was not induced after the treatment by TGFβ and IL-6 [85]. The combination of IL-23 and IL-1β stimulated the Th17 differentiation from CD4+ naive T cells, while the IL-23 induced IL-17 and IL-22 production were reduced by the effect of TGFβ and IL-6 [86]. TGFβ is not able to induce human Th17 development [84–86]. Interestingly, TGFβ may serve as an indirect inducer of Th17 development via the inhibition of IL-1β and IL-23 induced T-bet expression, IFNγ production, and Th1 cell differentiation of CD161+ precursors [87]. According to other observations, the TGFβ and IL-21 are necessary for the development of Th17 cells from naive cells [88].

The CD161+ precursor cells differentiate to mature Th17 cells after IL-1β and IL-23 stimulus. These cells express T-bet, IL-12Rβ2, CCR6, CD161 and RORC2 [81, 89, 90]. Two functionally different IL-17 producing memory T cell populations were also observed (Fig. 2b). CCR6 and CCR4 are expressed on a homologue population of IL-17 producing cells; the IL-17/IFNγ double producers like Th1 cells express CXCR3 [89, 91], CCR6 and T-bet [89, 90]. The Candida albicans specific memory Th17 cells were shown to be CCR6+ CCR4+; however, the CCR6+ CXCR3+ cells were specific for Mycobacterium tuberculosis [89, 90]. Zielinski and her colleagues described that Candida albicans and Staphylococcus aureus-primed Th17 cells produced different cytokines. C. albicans-primed cells produced IL-17 and IFN-γ, while S. aureus-specific Th17 cells produced IL-17 and IL-10 [92]. The role of AHR in the functionally different IL-17 producing human T cells needs to be investigated.

Transcriptional regulation of mouse Th17 differentiation

The transcription factors regulating Th17 cell differentiation are: the RORγt/RORC2, the AHR (see below), and the non-specific positive regulator STAT3. The differentiation of IL-17 producing T cells in mice is controlled by RORγt, which is encoded inside the RoRc locus and expressed by immature lymphocytes [93–95]. RORγt has an essential role in the lymphoid organogenesis; furthermore, it controls the thymopoiesis and the apoptosis of the thymocytes. In RORγt-deficient mice, the absence of lymph nodes and Peyer’s patches and also the infiltration of Th17 cells were observed [96]. In TGFβ and IL-6 primed murine cells, the RORγt expression is regulated by STAT3, which is activated by IL-6, IL-21, and IL-23. The TGFβ, IL-6, and IL-23-stimulated IL-17 secreting phenotype is also regulated by STAT3 [97–99]. RORγt alone is sufficient for IL-17 production, and STAT3 preferably contributes to the adequate Th17 phenotype. High number of IL-17+ cells and high IL-17 expression were observed in RORγt+ cells upon the activation of STAT3 [77, 98, 99]. Th17 cell differentiation, including RORγt expression, IL-21 production, and IL-23R expression are induced by low TGFβ concentration in the presence of IL-6 [75, 100]. STAT3 induces several important Th17-related genes including IL17A, IL17F, IL21, IL21R, IL23R and regulates the expression of other Th17 related transcription factors [e.g., RORγt, interferon regulatory factor 4(IRF4), and basic leucine zipper transcription factor (BATF)] [79, 101].

Transcriptional regulation of human Th17 differentiation

Human Th17 cells express (RORC2), which is an orthologue of murine RORγt [84, 86, 90, 102, 103]. The overexpression of RORC in naive T cells promotes the Th17 phenotype via induction of IL-17A, IL-17F, IL-26 production, and CCR6 expression, but downregulates IFNγ secretion. The overexpression of RORC2 was not associated with the increased expression of IL-22, CCR4, and CCR2 [102]. In addition, the overexpression of RORC2 is sufficient not only for the Th17-related cytokine production (IL-17, IL-22, IL-6, and TNF-α), but also for the chemokine receptor expression (CCR6 and CCR4 but not CXCR3) [104]. The IL-17 producing cells differentiate from CD161+ precursors, interestingly the expression of CD161 is upregulated by RORC2.

Th17/Th1 cells are phenotypically halfway towards Th1 cells, but they have many “Th17-like” properties such as RORC2 expression, IL-17 production, and cell surface markers [87]. The CD161+ cells are common precursors of both Th17 and Th1 differentiation (Fig. 2b) and both pathways can be induced by IL-1β and IL-23 [84, 87, 105]. IL-12 promotes the Th1 pathway via reduction of IL-17 and induction of IFNγ producing cells while the number of double producers is not altered. In this IL-17+ IFNγ+ population, the IL-22 and/or IL-17F producing cells are decreased by IL-12 [105]. In addition, TGFβ inhibits Th1 development via inhibition of T-bet expression; thus, indirectly promotes the Th17 differentiation [87].

Mouse Th17 differentiation and AHR

In mice, AHR shows ubiquitous expression in the immune system, including high expression in several immunologically important tissues and cells [106]. In murine Th17 cells, the receptor is highly expressed, there is a slight expression in regulatory T (Treg) cells while it is not detectable in naïve Th1 and Th2 cells [107–109]. Marc Veldhoven and his colleagues described that natural agonists of AHR are required for the optimal Th17 cell differentiation [110].The IL-17 production depends on the RORγt and RORα expression, while the IL-22 production appears to be less ROR dependent [111]. The ligand-dependent AHR signalization plays a major role in the regulation of IL-22 production of CD4+ T cells [109, 112]. The STAT proteins are important factors in the differentiation of helper T cell subpopulations [97]. STAT signalization is regulated by AHR signalization; thus, indirectly controls Th17 cell differentiation [107]. The IFNγ and IL-27 induced STAT1 activation is selectively regulated by AHR, which can suppress Th17 cell differentiation under Th17 cell polarizing conditions (in the presence of TGFβ+ IL-6 or TGFβ+ IL-21). AHR is able to bind STAT1 and STAT5, but not STAT3 or STAT6, and negatively regulates the Th17 differentiation [107]. The presence of TGFβ is required for AHR expression, by contrast, the RORγt expression is also induced without TGFβ signaling (Fig. 2a). The AHR expression was observed only in the non-pathogenic conventional Th17 cells but not in the IL-23 induced Th17 cells [79]. Interestingly, both Th17 and Treg cells express AHR in mice, but the receptor has a ligand-specific effect on the cells. An increased Th17 cell number was observed after the treatment of endogen ligands such as the 6-formylindolo[3,2-b]carbazole (FICZ), while Treg induction was described in the presence of exogen ligands like TCDD [108]. The effect of AHR also depends on the expressing cell and the origin of the activating ligand. This regulation may represent a way to avoid the potential harmful consequences of the AHR ligands. Endogen ligands promote Th17 development to eliminate pathogens via inflammation, while exogen ligands support Tregs, protecting from the autoimmune processes, elicited by the overstimulated Th17 cells [113]. The mortality of the AHR-deficient mice generated by Pedro M. Fernandez-Salguero and his colleagues was 50 %. A decreased accumulation of lymphocytes was observed in the spleen and lymph nodes but not in the thymus in these animals. Although the AHR-deficient mice had reduced liver size (by 50 %) and were resistant to dioxin exposure, high doses of dioxin caused limited vasculitis and scattered single cell necrosis in the livers and lungs of these animals [114, 115].

Human Th17 cell differentiation and AHR

AHR is highly expressed in several human tissues such as lung, heart, kidney, liver, esophagus, pancreas, placenta, testicle, thymus gland, and retina [116, 117]. AHR is also highly expressed in synovial tissues of RA patients which are regulated by TNFα. The AHR agonist TCDD treatment increases the expression of IL-1β and IL-6 of the synovial cells [84, 88, 118]. The IL-17 and IL-22 production of CD4+ T cells are also modulated by AHR [119]. The increased AHR expression was correlated with the inflammatory responses in allergic rhinitis [120]. A non-toxic AHR ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) upregulated AHR in healthy controls and inhibited the Th17 differentiation and the production of IL-17 and IL-22 both in allergic rhinitis patients and healthy donors [120]. TCDD also regulates the IL-22 production of IL-22 single positive cells via AHR binding. Furthermore, TCDD decreases the IL-17 production, RORC2 expression and IL-23R expression, and increases IL-22 production in an IL-23 and IL-1β-independent way [121].

The role of AHR in RORγt+ innate lymphoid cells

AHR is expressed by the RORγt+ innate lymphoid cells (ILCs), and contributes to the formation of intestinal lymphoid follicules and to the expansion of RORγt+ ILCs in mice. The expression of Kit is stabilized by AHR-mediated transcription, which also correlates with the postnatal expansion of RORγt+ ILC cell pool [122]. The number of ILC22 cells is significantly decreased in the AHR KO mice, leading to decreased production of IL-22. These animals lack postnatal but not embryonic ‘imprinted’ cryptopatches and isolated lymphoid follicles (ILFs), indicating that AHR is crucial for the development of postnatal intestinal lymphoid tissues [123]. AHR ligands, especially cruciferous vegetables from Brassicaceae family, are essential to maintain the population of intraepithelial lymphocytes (IELs) via AHR signalization in the skin and intestine in mice. IELs highly express AHR and they represent a first line of defense of epithelial barriers and wound repair. The reduced AHR activity in mice causes reduced antimicrobial capacity (against Bacteroidetes species) [124, 125]. AHR is also expressed by other innate IL-17 producing cells such as lymphoid tissue inducer-like cells (LTi-like cells), gamma delta T cells (γδ T) cells, and NK cells. These innate sentinel cells represent a first line of the defense against pathogens, and they have a primary role in the proper formation of lymphoid tissues. In addition, the expression of AHR enables these cells to respond to environmental effects [123, 126–128].

Aryl hydrocarbon receptor ligands and Th17 cells

Several AHR agonists and antagonists regulate the Th17 lymphocyte differentiation and activation and may contribute to the pathogenesis of numerous inflammatory diseases (Tables 1, 2).

Table 1.

The chemical structure of the AHR ligands in relation to Th17 cell development (↑ enhance; ↓ inhibit)

Receptor ligand	Chemical name	Action	Effect on Th17 development	2D structure
TCDD [108]	2,3,7,8-tetrachlorodibenzo-p-dioxin	Exogen agonist	↓
CH-223191 [116]	1-methyl-N-{2-methyl-4-[2-(2-methylphenyl)diazen-1-yl]phenyl}-1H-pyrazole-5-carboxamide	Synthetic antagonist	↓
B[a]P [109]	Benzo[alpha]pyrene	Exogen agonist	↑
3-MC [109]	3-Methylcholanthrene	Exogen agonist	↑
Leflunomide [118]	5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide	Exogen agonist	↓
ITE [120]	1′H-indole-3′-carbonyl-thiazole-4-carboxylic acid methyl ester	Endogen agonist	↓
FICZ [126]	6-Formylindolo(3,2-b)carbazole	Endogen agonist	↑
L-Kynurenine (KYN) [167]	(S)-2-Amino-4-(2-aminophenyl)- 4-oxo-butanoic acid	Endogen agonist	↓
Kynurenic acid (KYNA) [167]	(4-hydroxyquinoline-2-carboxylic acid)	Endogen agonist	↑
Indoxyl 3-sulfate (I3S) [133]	1H-Indol-3-yl hydrogen sulfate	Endogen agonist	↑
Indole-3-carbinol (I3C) [168]	1H-Indol-3-ylmethanol	Natural agonist	↓
3,3’-Diindolylmethane (DIM) [168]	3,3′-methanediylbis (1H-indole)	Natural agonist	↓
Curcumin [169]	(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione	Natural agonist/ antagonist	↓ (presumably indirectly)
trans Resveratrol (RES) [148]	3,5,4’-trihydroxy-trans-stilbene	Natural agonist/ antagonist	↓ (high concentration) ↑ (low concentration)
Polydatin (POLY) [148]	resveratrol-3-O-β-mono-d-glucoside	Modified natural antagonist	↑ (high concentration)
Baicalin [158]	(2S,3S,4S,5R,6S)-6-(5,6-dihydroxy-4-oxo-2-phenyl-chromen-7-yl)oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid	Natural agonist	↓
alpha-naphthoflavone (α-NF) [170]	2-phenylbenzo[h]chromen-4-one	Exogen antagonist	↓

Table 2.

AHR ligands linkage with human autoimmune diseases and animal models related with Th17 development

AHR ligand	Ligand type	Sources of ligand	Cell type/animal model used	Observed effect	Relevant diseases	Biological relevance in the pathology of disease
TCDD	Agonist	Combustion products, forest fire, cigarette smoke	Fibroblast-like synoviocyte cell line (MH7A)	Enhanced IL-1 mRNA	Rheumatoid arthritis	Aggravate [112]
			RA patient-derived synoviocites	Upregulated IL-1β, IL-6 and IL-8 production	Rheumatoid arthritis and osteoarthritis	Aggravate [105]
			2,4,6-trinitrobenzenesulfonic acid (TNBS) murine model of colitis	Decreased IL-6 and induced FoxP3+ Tregs	Inflammatory bowel disease	Suppress [164]
			C57BL/6 mice	Induced expansion of CD4+ CD25+ Foxp3+ Treg population	Experimental autoimmune encephalomyelitis	Suppress [95]
B[a]P	Agonist	Wood burning, exhaust fumes (especially diesel engine), charbroiled food, cigarette smoke	Fibroblast-like synoviocyte cell line (MH7A)	Enhanced IL-1 expression	Rheumatoid arthritis	Aggravate [112]
			Human monocyte-derived DCs	Reduced IL-6 production	Rheumatoid arthritis	Contribute to pathogenesis [165]
3-MC	Agonist	Combustion products	Fibroblast-like synoviocyte cell line (mh7a)	Enhanced IL-1 expression	Rheumatoid arthritis	Aggravate [112]
ITE	Agonist	Originally isolated from porcine lung	Murine T cells from thymus and mesenteric lymph nodes	Induced FoxP3+ Treg cells	Collagen-induced arthritis	Suppress [121]
			PBMCs from AR patients	Inhibited Th17 differentiation and production of IL-17 and IL-22	Allergic rhinitis	Suppress [107]
			DCs and CD4+ T cells from AR patients	Inhibited IL-1β and IL-6, induced IL-10 secretion by DCs, inhibited IL-17 and induced IL-10 expression and by CD4+ T cells and Th17 cell expansion in vitro	Allergic rhinitis	Suppress [123]
			monocyte-derived DCs and CD4+ T cells from BD patients	Inhibited production of IL-1β, IL-6, IL-23, TNFα and induced IL-10 by DCs and inhibited Th17 response	Behcet’s disease	Suppress [122]
FICZ	Agonist	Tryptophan photoproduct	CD4+ T cells from B6 mice and human	Increased expression of Il17a, Il17f and Il22	Experimental autoimmune encephalomyelitis	Aggravate [94]
			Lamina propria mononuclear cell from IBD patients and TNBS murine model of colitis	Upregulated production of IL-22	Inflammatory bowel disease	Suppress [167]
KYNA	Agonist	Generated from tryptophan by enzymatic process via kynurenine pathway	CD4+ T cells from BALB/c mice	Increased production of IL-17	Autoimmune gastritis	Aggravate [132]
I3S	Agonist	Originate from a tryptophan metabolite indole by intestinal bacteria	T cells from BALB/c mice	Increased phosphorylation of STAT3 and stimulated expression of RORγt, and in vitro Th17 differentiation	Collagen-induced arthritis	Aggravate [136]
I3C	Agonists	Generated from tryptophan from cruciferous vegetables (broccoli, brussel sprouts, cabbage, cauliflower, collard greens, sprouts, kale)	T cells from C57BL/6 mice	Increased number of Tregs and reduced number of Th17 cells	Experimental autoimmune encephalomyelitis	Suppress [138]
DIM
RES	Antagonist/agonist	Polyphenolic phytoalexin from red grape, red wine, cacao, peanut, mulberries, and pines	Lymphocytes from DBA1 mice	Inhibited production of IL-6, IL-17 and Th17 cell differentiation	Collagen induced arthritis	Suppress [166]
			Splenic and brain derived mononuclear cells and macrophages from SJL/J mice	Induced number of IL-17+ IL-10+ T cells and increased IL-12/23 p19 and p35 production by macrophages, decreased expression of IL-6 and IL-12/23p40 expression by macrophages	Experimental autoimmune encephalomyelitis	Suppress [151]
			C57BL/6 mice and mouse T lymphoma cell line (EL4)	Increased expression of FoxP3	Experimental allergic encephalomyelitis	Suppress [150]
Baicalin	Agonist	Flavone type flavonoid in the genus Scutellaria (e.g., Blue skullcap)	CD4+ T cells from C57BL/6 (B6) and lupus-prone MRL/lpr mice	Inhibited in vitro and in vivo differentiation of Th17, inhibited expression of CCR6, IL-6 receptor and RORγt, upregulated expression of Foxp3 and down-regulated RORγt-mediated IL-17	Lupus nephritis	Suppress [158]
α-NF	Antagonist	Flavone type flavonoid	Fibroblast-like synoviocyte cell line (MH7A)	Suppressed IL-1 expression via inhibition of B[a]P and 3-MC	Rheumatoid arthritis	Suppress [112]

Exogen ligands and xenobiotics

The typically carcinogenic and teratogenic exogenic ligands and xenobiotics are originated from the environment due to anthropogenic influence [129].

Halogenated dioxins (HAHs) and their congeners

HAHs are mainly derived from industrial activity and halogenation makes them to be metabolically and environmentally stabile. They are generally AHR agonists with different binding affinity, especially if the lateral rings are halogenated. TCDD, one of the best known AHR ligands, belongs to this group (Tables 1, 2) [130]. As it was previously described by Ramirez and co-workers, in vitro TCDD treatment of human PBMC increased the number of human IL-22 producing cells; however, decreased the IL-17 production and RORC2 expression [121]. In vivo TCDD treatment promoted the Treg differentiation and inhibited the Th17 differentiation in mice [108, 131]. The IL-1β mRNA level was enhanced in several different human cell lines, including fibroblast-like synoviocytes (MH7A) [132], keratinocytes [133] and endometrial stromal cells [134] after TCDD exposure.

A synthetic ligand, 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191), was identified from a chemical library as a potent AHR antagonist (Tables 1, 2). In vitro treatment of CH-223191 inhibited TCDD-induced transcription of AHR [135]. CH-223191, unlike most dietary compounds, is a pure antagonist, including flavones, which act both as agonists or antagonists on Th17 development, in a concentration-dependent way [110]. Interestingly, CH-223191 is a ligand selective AHR antagonist which only inhibits the binding of HAHs to AHR, and does not alter the binding of other AHR ligands [136].

Polycyclic aromatic hydrocarbons (PAHs)

PAHs represent a group of AHR agonists (less effective inducers of the AHR signalization than TCDD), which originate mainly from soot, grilled, or smoked food, smoke exhaust, and cigarette smoke. They are composed of four or more conjugate benzene rings [130]. The carcinogenic effect of benzo[alpha]pyrene (B[a]P) (Tables 1, 2), similarly to TCDD, is associated with the AHR activation. AHR knockout mice was resistant to the topical or subcutaneous B[a]P injection-induced tumor induction [137]. The IL-6, IL-1β mRNA level is upregulated in human MH7A cells by B[a]P and 3-MC, which also belongs to this group (Table 1) [132].

Leflunomide

Leflunomide, a widely used disease modifying anti-rheumatic drug (DMARD) in RA, is a potent AHR agonist (Table 1). Unlike its metabolite teriflunomide (A771726), leflunomide induced the translocation of the AHR to the nucleus and the induction of the AHR target genes in both human HepG2 and mouse WT Hepa1 cells [138]. The number of FoxP3+ Tregs and the IL-10-producing cells were increased, while the number of IL-17 and IL-23 producing, presumably Th17 cells were reduced in both murine peripheral blood and kidney cells following in vivo leflunomide treatment [139].

Endogen ligands

ITE

The AHR agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was first isolated from porcine lung (Table 1, 2) [140]. Treatment with ITE promoted the generation of FoxP3+ Treg cells in vivo and suppressed EAE in the mouse model. ITE treatment also induced the generation of tolerogenic dendritic cells that produce low levels of proinflammatory cytokines (IL-1β, IL-6, IL-12, IL-23), osteopontin, high levels of TGF-β1 and IL-10, and support the generation of FoxP3+ Tregs in vitro, via AHR activation [141]. ITE treatment of DCs, isolated from healthy donors and from patients with Bechet’s disease (BD), inhibited the Th17 cell differentiation and activation. ITE profoundly altered the cytokine production of DCs from active BD patients; the production of IL-1β, IL-6, IL-23, and TNFα were significantly inhibited while the IL-10 production was increased upon ITE treatment [142]. According to recently published data, the expression of AHR was increased and correlated with the clinical parameters in allergic rhinitis. ITE inhibited the expansion of Th17 cells and decreased the production of IL-17 in the samples of patients with allergic rhinitis [120, 143].

Dietary compounds

The anti-inflammatory properties of several dietary compounds including flavonoids and their derivatives (herbs, vegetables and fruits) might be explained by their effects on the AHR [144].

Tryptophan metabolites and derivatives

The essential amino acid tryptophan plays a central role in the Th17 cell development. The high affinity AHR agonist 6-formylindolo(3,2-b)carbazole (FICZ) is generated from tryptophan through photo-oxidation (Tables 1, 2) [145]. As it was mentioned earlier, natural AHR agonists were shown to be required for the optimal Th17 cell differentiation [110]. AHR is expressed both in mouse and human Th17 cells, and the activation of AHR with FICZ treatment promotes the Th17 cell expansion and IL-17 production in vitro [109]. Importantly, normal laboratory lightning may also induce the generation of FICZ, potentially leading to AHR activation in the cultured cells [146].

Tryptophan is also metabolized via the kynurenine (KYN) pathway. In mammals, l-tryptophan is oxidized into N-formylkynurenine first, either by the indoleamine 2,3-dioxygenase 1 (IDO1), or by the IDO2 or by the tryptophan 2,3-dioxygenase (TDO-2) enzymes. N-formylkynurenine is further degraded into L-kynurenine (KYN) by formylkynurenine formamidase (FKF), then L-kynurenine might be irreversibly transaminated into kynurenic acid (KYNA) by kynurenine aminotransferases (KATs) (Fig. 3) [147, 148].

Fig. 3.

The tryptophan originated AHR ligands were indicated red bold letters. 3-HK: 3-hydroxykynurenine, DIM: 3,3′-diindolylmethane, FICZ: 6-formylindolo(3,2-b)carbazole, FKF: formylkynurenine formamidase, I3C: indole-3-carbinol, I3S: indoxyl 3-sulfate, IDO1: 2,3-dioxygenase 1, IDO2: 2,3-dioxygenase 2, KATs: kynurenine aminotransferases, KMO: kynurenine 3-monooxygenase, KYN: kynurenine, KYNA: kynurenic acid, TDO: tryptophan 2,3-dioxygenase [147, 148, 151, 154, 155, 158, 159]

Both KYN and KYNA are endogen agonists of the AHR (Table 1 and 2). KYN is a potent long-acting AHR ligand which directly activates the receptor. In mice, the differentiation of FoxP3+ Tregs, but not the Th17 cells, was promoted by KYN via AHR-dependent pathway. This effect of KYN was further potentiated by TGFβ [149]. KYNA induces IL-6 production in synergism with IL-1β in breast cancer cell line MCF-7 [150]. Kynurenine might be metabolized into 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO) and by kynureninase enzymes (Fig. 3) [151]. KMO enzymes are preferentially expressed by murine Th17 cells and contribute to the differentiation of Th17 cells in vitro. If the KMO enzyme is inhibited, the KYNA is highly formed from KYN in the Th17 cells by KATs. The Th17-driven inflammation is enhanced by this process in an AHR-dependent way [152].

Indoxyl 3-sulfate (I3S), another potent AHR agonist (Tables 1, 2; Fig. 3), is an uremic toxin, which is not completely cleared from the blood of hemodialyzed patients, due to its albumin binding capacity. I3S is synthetized in the liver from the intestinal bacterial metabolite indole [153, 154]. Indole is metabolized in the intestinal tract from dietary tryptophan by the tryptophanase enzymes of the intestinal bacteria [155]. In mice, I3S promotes Th17 cell differentiation via the increased RORγt expression and STAT3 phosphorylation in an AHR-dependent way. Furthermore, the treatment of I3S aggravated EAE by increasing the number of Th17 cells in vivo [153, 156]. The kynurenine/tryptophan ratio was found to be increased in the sera of patients with RA [157]. These data suggest that tryptophan metabolites regulate the development of autoimmunity, through mediating the AHR activation.

Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) (Tables 1, 2; Fig. 3) are also potent AHR agonists, which are originated in dietary tryptophan in cruciferous vegetables, such as broccoli, brussels sprouts, cabbage, cauliflower, collard greens, sprouts, and kale) [158]. Glucobrassicins are degraded to I3C from cruciferous vegetables via metabolism which is further condensated to DIM under acidic conditions [159]. The Th17 differentiation was inhibited, while the generation of Tregs was promoted in vivo and in vitro in mice by both I3C and DIM via an AHR-dependent pathway. The previously mentioned AHR antagonist CH223191 was capable to reverse the Th17 suppressing effects of I3C and DIM in vivo; however, Th17 differentiation was also inhibited by this antagonist in vitro [158] (Fig. 4).

Fig. 4.

The aryl hydrocarbon receptor as a potential regulator of inflammation via synchronize the environmental effects and the dietary compounds which cooperates with genetics

Curcumin

Curcumin a lipophilic polyphenol is well known as a traditional (Ayurvedic) medicine derived from the rhizome of the plant Curcuma longa (turmeric) (Table 1) [160]. AHR shows both agonistic and antagonistic effect in different cells, but acts as antagonist in the presence of HAHs and PAHs in both human breast carcinoma cell line MCF-7 and mouse hepatoma (Hepa-1c1c7) cells [161, 162]. Curcumin has anti-cancer, antioxidant, and anti-inflammatory effects and it may protect the skin, kidneys, brain, heart, liver, and lungs from oxidative effects [163].

Although the direct role of curcumin on the AHR was not studied yet, it inhibited the expression of proinflammatory cytokines (TNFα, IL-1β, IL-6, IL-12, and IFNγ) [164] and the IL-6-induced activation, translocation, and phosphorylation of STAT3 in a dose-dependent manner in head and neck squamous cell carcinoma (HNSCC) cell line [165]. Curcumin stimulated the TCDD-induced AHR translocation to the nucleus and facilitated the heterodimerization with ARNT but it inhibited the binding to DRE in the nucleus in mouse Hepa-1c1c7 cells. These data suggest that curcumin suppresses the transformation of AHR by inhibiting its phosphorylation [161].

Resveratrol (RES)

Resveratrol is a polyphenolic phytoalexin, which can be found in red grape, red wine, cacao, peanut, mulberries, and pines. It has cis and trans isoforms. The trans isomer is more stable and more bioactive. RES may act both as agonist and antagonist of the AHR receptor (Tables 1 and 2). Resveratrol binds to the AHR and promotes its translocation to the nucleus, but does not induce subsequent transactivation as a competitive antagonist in human carcinoma cell line [166]. The anti-inflammatory effects of resveratrol are associated with its effect on the Th17 development [167–169]. The IL-17 production of human peripheral blood mononuclear cells (PBMCs) was stimulated by low concentrations of RES (0,01 µg/ml), while higher concentrations (20 µg/ml) had inhibitory effect. Trans-resveratrol is easily converted into the less stable cis form by the effect of UV radiation unlike polydatin (resveratrol-3-O-β-mono-d-glucoside, POLY) (Tables 1, 2). POLY is a major glucoside derivative of RES which more effectively inhibits the IL-17 production of human PBMCs than RES [167, 168]. STAT3 activity was shown to be modulated by RES in human leukemia cell lines (Jurkat, SUP-B15, and Kasumi-1) [169]. Resveratrol induced the AHR expression in activated T cells in vitro and suppressed the inflammation in mice with induced experimental allergic encephalomyelitis [170]. In these animals, increased IL-17+ IL-10+ cell number, decreased IL-6 expression by macrophage and induced FoxP3 and IL10 expression were observed after oral exposition of RES [170, 171]. Thus, AHR-dependent inhibition of IL-17 production may have important role in the protective effect of moderate alcohol consumption in RA [172].

Flavonoids

Flavonoids are naturally occurring plant metabolites [173]. Their agonistic or antagonistic effect on the AHR largely depends on their actual concentration and on the affected cell type [174]. Many flavonoids have antioxidant, anti-inflammatory, and anti-cancer activity which make them suitable for use in natural therapy [175]. Baicalin is a flavone type flavonoid which originates from the roots of Scutellariae Radix (Tables 1 , 2). Baicalin inhibited the dioxin-induced activation of AHR, by contrast it may serve as a receptor antagonist as well [176, 177]. The Th17 development was inhibited by baicalin both in vivo and in vitro in mice. The IL-17 production and RORγt expression were inhibited, while FoxP3 expression was upregulated by baicalin in vitro. The expression of CCR6 and IL-6 receptor were also suppressed by baicalin in vivo, which may contribute to the decreased infiltration of Th17 cells into the inflamed kidney tissue in lupus-prone MRL/lpr mice [178]. The AHR antagonist alpha-naphthoflavone (α-NF) inhibits the TCDD-induced AHR signalization by forming an inactive complex with AHR (Table 1, 2) [179]. The B[a]Pand 3-MC induced IL-1β mRNA expression of human MH7A cells was also inhibited by α-NF [132].

AHR ligands linkage with autoimmune diseases

Several endogenous and exogenous AHR ligands regulate the differentiation and activation of Th17 cells (Table 2), thereafter the activation of the AHR may shape the immune response in infections, tumors, and autoimmune diseases. AHR appears to represent a link between environmental effects (smoking, dietary compounds, alcohol consumption, air pollutants, etc.) and the immune responses. According to the latest results, AHR has a prominent role in the antimicrobial defense against both acute and chronic bacterial infections. AHR is capable of sensing the bacterial pigments as pathogen-associated molecular patterns and regulates inflammation in the infected organ [180].

Cigarette smoke

Cigarette smoke, a major risk factor for RA [181], contains significant amounts of several AHR ligands including HAHs such as TCDD and PAHs like B[a]P and 3-MC. Cigarette smoking appears to be a risk factor for RA, especially in patients, who carry the shared epitope (SE), representing a well-established gene–environmental interaction [182]. AHR may provide a link between smoking and autoimmunity in RA [118, 183]. The TNF-α induced AHR expression in RA synovial tissue is referring to the potential pathogenic role of AHR activation in RA. TCDD upregulates the expression of proinflammatory cytokines (IL-1β, IL-6, IL-17, IL-22) via AHR activation, suggesting that TCDD exposure contributes to the pathophysiology of RA. On the other hand, the development of Tregs was upregulated by TCDD in murine models of other inflammatory diseases such as inflammatory bowel disease (IBD) or EAE [108, 184]. The expression of IL-1 was also induced by PAHs: B[a]P and 3-MC [132]. Decreased IL-17A gene expression was measured in the synovial samples of smoker RA patients compared to the non-smokers. AHR is mainly expressed in the monocyte-derived early differentiating DCs. B[a]P exposure decreased the toll-like receptor agonist polyinosinic: polycytidylic acid (Polyl:C) induced IL-6 expression in DCs [185].

Norture

AHR appears to have a central role in regulating the inflammatory processes and it has numerous ligands in both food and drink. Tryptophan from nutriment is metabolized via either photo-oxidation or enzymatic pathways, which leads to the generation of different AHR ligands. The IL-17 and IL-22 expressions are induced in mice by a tryptophan photoproduct FICZ, which aggravates the development of EAE [109]. Other tryptophan metabolites such as I3C and its derivative DIM support the generation of Tregs, which suppress the inflammation in EAE [158]. EAE was also suppressed by resveratrol [171]. Interestingly, the IL-17 production of human PBMCs was inhibited by higher resveratrol concentrations [167]. However, the number of IL-17+ IL-10+ producing cells was not decreased in mice during EAE, in addition, FoxP3 expression was upregulated in experimental allergic encephalomyelitis by resveratrol [170, 171]. Collagen induced arthritis in mice is also suppressed by resveratrol (via the inhibition of IL-6 and IL-17 production) [186], by contrast it was aggravated through the inhibition of RORγt expression and STAT3 phosphorylation by I3S [156]. The 3-HK pathway, one of the KYN metabolization pathways, is catalyzed by a Th17-specific enzyme KMO, which is upregulated in Th17 cells. The inhibition of KMO enzyme leads to the aggravation of the autoimmune responses and promotes Th17 differentiation in an AHR-dependent way. The KMO enzyme activation may represent a self-limiting mechanism in the regulation of inflammation [152]. Several flavonoids, such as baicalin, are also AHR ligands and have anti-inflammatory roles through the inhibition of Th17 development and the promotion of Tregs [178].

Conclusion

Numerous endogen and exogen AHR ligands regulate the differentiation and activation of Th17 and Treg cells; thereafter, the activation of the AHR may shape the immune response in infections, tumors, and autoimmune diseases. AHR appears to represent a link between environmental effects (smoking, dietary compounds, alcohol consumption, air pollutants, etc.) and the immune response. Several AHR ligands contribute to the inflammation via the promotion of the Th17 differentiation such as cigarette smoke components (PAHs and HAHs), or tryptophan derivatives (I3S, KYNA). By contrast, other AHR ligands suppress inflammation and may support the Treg development. AHR ligands can be found in the environment as pollutants or in different foods such as flavonoids, fruits, vegetables, and herbs. Some of these directly inhibit the Th17 development like baicalin, resveratrol, I3C and DIM, while others indirectly block the Th17 induced inflammation such as curcumin and αNF. A better understanding of the immunomodulatory effects of the AHR ligands may contribute to the development of new medications of immune-mediated diseases.

Abbreviations

3-HK

3-Hydroxykynurenine

3-MC

3-Methylcholanthrene

AHR

Aryl hydrocarbon receptor

AHRR

Nuclear AHR repressor

AR

Androgen receptor

ARNT

Aryl hydrocarbon receptor nuclear translocator

B[a]P

Benzo[alpha]pyrene

BBB-ECs

Blood–brain barrier endothelial cells

BD

Bechet’s disease

bHLH/PAS

Basic helix–loop–helix/Per–Arnt–Sim

CBP/P300

CREB-binding protein/E1A binding protein p300 protein

CCL20

Chemokine (C–C motif) ligand 20

CCR6

Chemokine receptor 6

CH-223191

2-Methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide

c-MAF

V-Maf avian musculoaponeuroticfibrosarcoma oncogene homolog

CNS

Central nervous system

CXCL1

Chemokine (C-X-C motif) ligand 1

CYP1A1

Cytochrome P450, family 1, subfamily A, polypeptide 1

DCs

Dendritic cells

DIM

3,3′-Diindolylmethane

E2

17β-Estradiol

EAE

Experimental autoimmune encephalomyelitis

eNOS

Endothelial NO synthase

ER

Estrogen receptor

ERE

Estrogen response element

ERα

Estrogen receptor alpha

FICZ

6-Formylindolo(3,2-b)carbazole

FoxP3

Forkhead box P3

FKF

Formylkynurenineformamidase

G-CSM

Granulocyte colony-stimulating factor

GM-CSF

Granulocyte–monocyte colony-stimulating factor

HAHs

Halogenated-dioxins and their congeners

HSP90

Heat shock protein 90

I3C

Indole-3-carbinol

I3S

Indoxyl 3-sulfate

IBD

Inflammatory bowel disease

IDO1

2,3-Dioxygenase 1

IDO2

2,3-Dioxygenase 2

IFNγ

Interferon gamma

ILC

Innate lymphoid cell

ILFs

Isolated lymphoid follicles

IELs

Intraepithelial lymphocytes

LTi

Lymphoid tissue inducer

IL-10

Interleukin 10

IL-1β

Interleukin-1 beta

ITE

2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester

KATs

Kynurenine aminotransferases

KLRB1

Killer cell lectin-like receptor B1

KMO

Kynurenine 3-monooxygenase

KYN

Kynurenine

KYNA

Kynurenic acid

LXR

Liver X receptor

LXRα

Liver X receptor alpha

LXRβ

Liver X receptor beta

MMP

Matrix metalloproteinase

MDR1

Multidrug resistance protein 1

MS

Multiple sclerosis

NES

Nuclear export signal

NF-1

Nuclear factor 1

NFκB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NK

Natural killer

NKT

Natural killer T

NO

Nitric oxide

p23

Prostaglandin E synthase 3

PAHs

Polycyclic aromatic hydrocarbons

PAS

PerArntSim

PBMCs

Peripherial blood mononuclear cells

PCBs

Planar polychlorinated biphenyls

POLY

Polydatin

PolylC

Toll-like receptor agonist polyinosinic:polycytidylic acid

PPARs

Peroxisome proliferator-activated receptors

PPARα

Peroxisome proliferator-activated receptor alpha

PPRE

PPAR response element

RA

Rheumatoid arthritis

RES

Resveratrol

RORC2

Retinoic acid-related orphan receptor variant 2

RORγt

RAR-related orphan nuclear receptor gamma t

SE

Shared epitope

SLE

Systemic lupus erythematosus

SOCS3

Suppressor of cytokine signaling 3

Srebp-1

Sterol regulatory element-binding protein 1

TAD

Transactivation domain

T-bet

T-box expressed in T cells

TBP

TATA-box-binding protein

TDO

Tryptophan 2,3-dioxygenase

TGFB1

Tumor growth factor beta 1

Th17

T helper 17

Th17(23)

IL-23 induced Th17 cells

Th17(β)

Conventional Th17 cells

TNBS

2,4,6-Trinitrobenzenesulfonic acid

TNFα

Tumor necrosis factor alpha

Tr1

Type 1 regulatory T

Treg

Regulatory T cell

UGT1A1

UDP glucuronosyltransferase 1 family, polypeptide A1

XAP2

Hepatitis B virus X-associated protein

XREs

Xenobiotic responsive elements

WY

WY-14643

α-NF

Alpha-napthoflavone

γδ T

Gamma delta T cells