Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma:From immune modulation to therapeutic opportunities

Esophageal squamous cell carcinoma(ESCC)is a substantial global health burden.Immune escape mechanisms are important in ESCC progression,enabling cancer cells to escape the surveillance of the host immune system.One key player in this process is the Aryl Hydrocarbon Receptor(AhR),which influences multiple cellular processes,including proliferation,differentiation,metabolism,and immune regulation.Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis,epithelial-mesenchymal transition,and immune escape.Targeting AhR signaling is a potential therapeutic approach for ESCC,with AhR ligands showing efficacy in preclinical studies.Additionally,modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention.This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.

Harnessing aryl hydrocarbon receptor dynamics:Unveiling therapeutic pathways in esophageal squamous cell carcinoma

This editorial discusses the insightful minireview by Rahmati et al.The minireview delves into the role of the aryl hydrocarbon receptor in the development and progression of esophageal squamous cell carcinoma,highlighting its potential as a promising therapeutic target.The authors concisely summarize the current understanding of how aryl hydrocarbon receptor modula-tion influences immune responses and the tumor microenvironment,offering fresh perspectives on therapeutic strategies.This editorial aimed to emphasize the significance of these findings and their potential impact on future research and clinical practices for the management of esophageal squamous cell carcinoma.

Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.

Constitutive aryl hydrocarbon receptor facilitates the regenerative potential of mouse bone marrow mesenchymal stromal cells

BACKGROUND Bone marrow mesenchymal stromal cells(BMSCs)are the commonly used seed cells in tissue engineering.Aryl hydrocarbon receptor(AhR)is a transcription factor involved in various cellular processes.However,the function of constitutive AhR in BMSCs remains unclear.AIM To investigate the role of AhR in the osteogenic and macrophage-modulating potential of mouse BMSCs(mBMSCs)and the underlying mechanism.METHODS Immunochemistry and immunofluorescent staining were used to observe the expression of AhR in mouse bone marrow tissue and mBMSCs.The overexpression or knockdown of AhR was achieved by lentivirus-mediated plasmid.The osteogenic potential was observed by alkaline phosphatase and alizarin red staining.The mRNA and protein levels of osteogenic markers were detected by quantitative polymerase chain reaction(qPCR)and western blot.After coculture with different mBMSCs,the cluster of differentiation(CD)86 and CD206 expressions levels in RAW 264.7 cells were analyzed by flow cytometry.To explore the underlying molecular mechanism,the interaction of AhR with signal transducer and activator of transcription 3(STAT3)was observed by co-immunoprecipitation and phosphorylation of STAT3 was detected by western blot.RESULTS AhR expressions in mouse bone marrow tissue and isolated mBMSCs were detected.AhR overexpression enhanced the osteogenic potential of mBMSCs while AhR knockdown suppressed it.The ratio of CD86+RAW 264.7 cells cocultured with AhR-overexpressed mBMSCs was reduced and that of CD206+cells was increased.AhR directly interacted with STAT3.AhR overexpression increased the phosphorylation of STAT3.After inhibition of STAT3 via stattic,the promotive effects of AhR overexpression on the osteogenic differentiation and macrophage-modulating were partially counteracted.CONCLUSION AhR plays a beneficial role in the regenerative potential of mBMSCs partially by increasing phosphorylation of STAT3.

Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer

AIM： To determine the functional significance of aryl hydrocarbon receptor （AhR） in gastric carcinogenesis, and to explore the possible role of AhR in gastric cancer （GC） treatment. METHODS： RT-PCR, real-time PCR, and Western blotting were performed to detect AhR expression in 39 GC tissues and five GC cell lines. AhR protein was detected by immunohistochemistry （IHC） in 290 samples： 30 chronic superficial gastritis （CSG）, 30 chronic atrophic gastritis （CAG）, 30 intestinal metapiasia （IN）, 30 atypical hyperplasia （AH）, and 70 GC. The AhR agonist tetrachlorodibenzo-para-dioxin （TCDD） was used to treat AGS cells. MTr assay and flow cytometric analysis were performed to measure the viability, cell cycle and apoptosis of AGS cells.RESULTS： AhR expression was significantly increased in GC tissues and GC cell lines. IHC results indicated that the levels of AhR expression gradually increased, with the lowest levels in CSG, followed by CAG, IM, AH and GC. AhR expression and nuclear translocation were significantly higher in GC than in precancerous tissues. TCDD inhibited proliferation of AGS cells via induction of growth arrest at the G1-S phase. CONCLUSION： AhR plays an important role in gastric carcinogenesis. AhR may be a potential therapeutic target for GC treatment.

The oral commensal Streptococcus mitis activates the aryl hydrocarbon receptor in human oral epithelial cells

Streptococcus mitis （S. mitis） is a pioneer commensal bacterial species colonizing many of the surfaces of the oral cavity in healthy individuals. Yet, not much information is available regarding its interaction with the host. We used examination of its transcriptional regulation in oral keratinocytes to elucidate some of its potential roles in the oral cavity. Transcription factor analysis of oral keratinocytes predicted S. mitis.mediated activation of aryl hydrocarbon receptor （AhR）, Activation and functionality of AhR was confirmed through nuclear translocation determined by immunofluorescence microscopy and real-time polymerase chain reaction with reverse transcription analysis of CYPIA1, the hallmark gene for AhR activation. Addition of Streptococcus mutans or Streptococcus gordonfi did not induce CYPIA1 transcription in the keratinocyte cultures. Introduction of an AhR-specific inhibitor revealed that S. mitis-mediated transcription of CXCL2 and CXCL8 was regulated by AhR. Elevated levels of pmstaglandin E2 （enzyme-linked immunosorbent assay） in supernatants from S. mitis-treated oral epithelial cells were also attenuated by inhibition of AhR activity. The observed AhR-regulated activities point to a contribution of S. mitis in the regulation of inflammatory responses and thereby to wound healing in the oral cavity. The concept that the oral commensal microbiota can induce AhR activation is important, also in view of the role that AhR has in modulation of T-cell differentiation and as an anti-inflammatory factor in macrophaees.

Activation of Aryl Hydrocarbon Receptor Prolongs Survival of Fully Mismatched Cardiac Allograft

Recent data suggest that activation of aryl hydrocarbon receptor （AhR） by its high-affinity ligand 2,3,7,8-tetrachlorodihenzo-p-dioxin （TCDD） results in expansion of regulatory T （Treg） cells and suppresses the development of autoimmune and allergic diseases in several models. Treg cells have been increasingly documented to suppress allograft rejection and even to establish stable long-term graft acceptance. However, the involvement of TCDD in the regulation of solid organ transplantation rejec- tion is largely unknown. Here, we examined whether activation of AhR with TCDD altered cardiac al- lograft rejection in an allogeneic heart transplant model. Recipient C57BL/6 （H-2b） mice were adminis- trated with a single intraperitoneal injection of TCDD, and the murine cardiac transplant models from BALB/c （H-2d） to C57BL/6 （H-2b） were built 24 h later. The complete cessation of cardiac contractility was defined as the observation endpoint. The effect of TCDD on T-cell proliferation was assessed by mixed lymphocyte reaction （MLR）. Histological and immunohistochemical analyses were performed to estimate the severity of rejection. The phenotype and cytokine profile of lymphocytes were analyzed by flow cytometry and enzyme-linked immunosorbent assay （ELISA）. Activation of AhR remarkably pro- longed the survival of cardiac allografts to more than 20 days. In vitro, TCDD ugregulated the fre- quency of CD4＋CD25＋Foxp3＋ Treg cells and suppressed the proliferation of T lymphocytes. In vivo, the prolonged survival time was associated with increased number of Treg cells in allografls and spleens Furthermore, the secretion of interferon-3, （IFN-3,） and interleukin-17 （IL-17） was reduced to less than 50% of that of the PBS treatment control group by TCDD treatment, whereas IL-10 was elevated to 10-fold of that of the PBS treatment control group. Collectively, our data indicate that activation of AhR with a single dose of TCDD significantly prolonged the survival of fully allogeneic cardiac grafts, and the mechanism underlying this effect might be involved in the induction of Treg cells.

Gene-environment interactions in male reproductive health： special reference to the aryl hydrocarbon receptor signaling pathway

Over the last few decades, there have been numerous reports of adverse effects on the reproductive health of wildlife and laboratory animals caused by exposure to endocrine disrupting chemicals （EDCs）. The increasing trends in human male reproductive disorders and the mounting evidence for causative environmental factors have therefore sparked growing interest in the health threat posed to humans by EDCs, which are substances in our food, environment and consumer items that interfere with hormone action, biosynthesis or metabolism, resulting in disrupted tissue homeostasis or reproductive function. The mechanisms of EDCs involve a wide array of actions and pathways. Examples include the estrogenic, androgenic, thyroid and retinoid pathways, in which the EDCs may act directly as agonists or antagonists, or indirectly via other nuclear receptors. Dioxins and dioxin-like EDCs exert their biological and toxicological actions through activation of the aryl hydrocarbon-receptor, which besides inducing transcription of detoxifying enzymes also regulates transcriptional activity of other nuclear receptors. There is increasing evidence that genetic predispositions may modify the susceptibility to adverse effects of toxic chemicals. In this review, potential consequences of hereditary predisposition and EDCs are discussed, with a special focus on the currently available publications on interactions between dioxin and androgen signaling.

Aryl Hydrocarbon Receptor is Involved in the Proinflammatory Cytokine Response to Cadmium

Objective To investigate involvement of the aryl hydrocarbon receptor(Ah R)in the immunomodulatory effects of cadmium(Cd).Methods The effect of Cd on Ah R activation(CYP1 A1 and CYP1 B1 m RNA expression)was examined in lung leukocytes of Cd-exposed rats(5 and 50 mg/L,30 d orally)and by in vitro leukocyte exposure.The involvement of Ah R signaling in the effects of Cd on the interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191.Results Cd increased CYP1 B1(in vivo and in vitro)and CYP1 A1(in vitro)m RNA,indicating Ah R involvement in the action of Cd.In response to Cd,lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels,but decreased IL-1βproduction due to reduced NLRP3.The Ah R antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response.The absence of Ah R reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high Ah R repressor m RNA level.Conclusion Ah R signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd.The relevance of the Ah R to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.

Blocking the Aryl Hydrocarbon Receptor Alleviates Myocardial Ischemia/Reperfusion Injury in Rats

Objective Restoring the blood perfusion of ischemic heart tissues is the main treatment for myocardial ischemia.However,the accompanying myocardial ischemia reperfusion injury(IRI)would aggravate myocardial damage.Previous studies have confirmed that aryl hydrocarbon receptor(AhR)is closely correlated to kidney and intestinal IRI.The present study aimed to explore the relationship between AhR and myocardial IRI.Methods An oxygen glucose deprivation/reoxygenation(OGD/R)model of H9c2 cells and an ischemia/reperfusion(I/R)model of Sprague-Dawley rat myocardium were established.OGD/R cells and myocardial IRI rats were treated with different concentrations of the AhR antagonist CH-223191 or agonist 6-formylindolo[3,2-b]carbazole(FICZ).Under the conditions of normoxia and hypoxia/reoxygenation,the activity of cardiomyocytes,lactate dehydrogenase(LDH)and cell reactive oxygen species(ROS)were detected.In rats,myocardial pathological damage and markers of myocardial injury were detected.Results According to the results of the cell viability,LDH and ROS tests in vitro,both CH-223191 and FICZ showed no myocardial protection under OGD/R conditions.However,the histological staining and analysis of myocardial injury marker LDH in vitro revealed that CH-223191 could significantly reduce the myocardial IRI.Conclusion AhR exhibited a different effect on myocardial IRI in vitro and in vivo.In vivo,CH-223191 could significantly alleviate the myocardial IRI,suggesting that inhibition of AhR may play a role in myocardial protection,and AhR may serve as a potential treatment target for myocardial IRI.

Aryl hydrocarbon receptor as a new therapeutic target for cancer and immune disorders

The aryl hydrocarbon receptor （AhR） was discovered more than three decades ago, and initially was char-acterized as a transcription factor with a role in xe-nobiotic metabolism. However, based on subsequent observations that AhR remains active under physiologi-cal conditions, exhibits constitutive expression during development, and has a high degree of conservation among species, it was hypothesized that AhR is re-sponsible for functions in addition to its role in detoxif-cation. Correspondingly, recent studies have elucidated novel physiological roles for this ligand-dependent transcription factor that link it to several pathways associated with disease development. In this review, studies are presented that support a role for AhR in cell proliferation, apoptosis, and immune homeostasis, thereby highlighting the therapeutic potential of this receptor for cancer and immune disorders.

Expression and role of aryl hydrocarbon receptor in Aspergillus fumigatus keratitis

●AIM:To observe the expression and role of aryl hydrocarbon receptor(Ah R)in the immune response of mouse cornea infected with Aspergillus fumigatus(A.fumigatus).●METHODS:Murine models of A.fumigatus keratitis were established by scraping the central epithelium of mouse cornea,daubing A.fumigatus on the cornea and covering with a contact lens.The mice were randomly divided into the control group and the A.fumigatus-infected(A.F.)group for 1,3 and 5 d respectively,which corneas were daily monitored by a slit lamp microscope and the clinical scores were also recorded timely after infection.In this study,immunofluorescence staining was used to detect the expression and localization of Ah R in mouse corneas,and the m RNA and protein of Ah R were detected by reverse transcription-polymerase chain reaction(RT-PCR)and Western blot.In addition,mouse peritoneal macrophages were stimulated by A.fumigatus with or without the pretreatment of Ah R antagonist CH223191 and Ah R agonist FICZ,and the tumor necrosis factor alpha(TNF-α),inducible nitric oxide synthase(i NOS),interleukin-10(IL-10)and Arg-1 m RNA were detected by RT-PCR.●RESULTS:According to the results of the slit light photography,it was clearly indicated that the corneal inflammation were the most severe and the clinical score became the highest as well on the 3 rd day after the infection of A.fumigatus.Contrasted with the control group,the expression of Ah R in the corneal epithelial cells infected with A.fumigatus was significantly increased detected by immunofluorescence staining.Ah R mainly expressed in the nucleus and cytoplasm of corneal epithelial cells.Consistent with the transcriptional level of Ah R m RNA,the expression level of Ah R protein reached the peak on the 3 rd day after infection which was detected by Western blot.Furthermore,RT-PCR showed that CH223191 up-regulated the expression of TNF-αand i NOS and down-regulated the expression of IL-10 and Arg-1 in peritoneal macrophages;inversely,FICZ reduced the expression of TNF-αand i NOS while elevated the expression of IL-10 and Arg-1.●CONCLUSION:Ah R is involved in the pathogenesis of A.fumigatus keratitis and induced immune protection in anti-A.fumigatus immune response by inhibiting M1 and increasing M2 phenotype macrophage-related inflammatory factors.

The Aryl Hydrocarbon Receptor: A Target for Breast Cancer Therapy

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in response to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is historically characterized for its role in mediating the toxicity and adaptive responses to these chemicals, however mounting evidence has established a role for it in ligand-independent physiological processes and pathological conditions, including cancer. The AhR is overexpressed and constitutively activated in advanced breast cancer cases and was shown to drive the progression of breast cancer. In this article we will review the current state of knowledge on the possible role of AhR in breast cancer and how it will be exploited in targeting AhR for breast cancer therapy.

Aryl hydrocarbon receptor:Linking environment to aging process in elderly patients with asthma

Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly individuals.It is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage,resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases.The effects of aging affect not only the elderly but also those of younger ages,posing significant challenges to global healthcare.Thus,understanding the molecular mechanisms associated with aging in different diseases is essential.One intriguing factor is the aryl hydrocarbon receptor(AhR),which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process.Here,we review the literature on several major hallmarks of aging,including mitochondrial dysfunction,cellular senescence,autophagy,mitophagy,epigenetic alterations,and microbiome disturbances.Moreover,we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures,particularly in relation to the immune system.Furthermore,we explore how aging hallmarks affect clinical characteristics,inflammatory features,exacerbations,and the treatment of asthma.It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.

Predicting Chemical Immunotoxicity through Data-Driven QSAR Modeling of Aryl Hydrocarbon Receptor Agonism and Related Toxicity Mechanisms

Computational modeling has emerged as a time-saving and cost-effective alternative to traditional animal testing for assessing chemicals for their potential hazards.However,few computational modeling studies for immunotoxicity were reported,with few models available for predicting toxicants due to the lack of training data and the complex mechanisms of immunotoxicity.In this study,we employed a data-driven quantitative structure–activity relationship(QSAR)modeling workflow to extensively enlarge the limited training data by revealing multiple targets involved in immunotoxicity.To this end,a probe data set of 6,341 chemicals was obtained from a high-throughput screening(HTS)assay testing for the activation of the aryl hydrocarbon receptor(AhR)signaling pathway,a key event leading to immunotoxicity.Searching this probe data set against PubChem yielded 3,183 assays with testing results for varying proportions of these 6,341 compounds.100 assays were selected to develop QSAR models based on their correlations to AhR agonism.Twelve individual QSAR models were built for each assay using combinations of four machine-learning algorithms and three molecular fingerprints.5-fold cross-validation of the resulting models showed good predictivity(average CCR=0.73).A total of 20 assays were further selected based on QSAR model performance,and their resulting QSAR models showed good predictivity of potential immunotoxicants from external chemicals.This study provides a computational modeling strategy that can utilize large public toxicity data sets for modeling immunotoxicity and other toxicity endpoints,which have limited training data and complicated toxicity mechanisms.

Norisoboldine, a natural aryl hydrocarbon receptor agonist, alleviates TNBS-induced colitis in mice, by inhibiting the activation of NLRP3 inflammasome

Although the etiology of inflammatory bowel disease is still tmcertain, increasing evidence indicates that the excessive activation of NLRP3 inflammasome plays a major role. Norisoboldine （NOR）, an alkaloid isolated from Radix Linderae, has previously been demonstrated to inhibit inflammation and IL-1,8 production. The present study was to examine the effect of NOR on colitis and the underlying mechanism related to NLRP3 inflammasome activation. Our results showed that NOR alleviated colitis symptom in mice induced by 2, 4, 6-trinitrobenzene sulfonic acid （TNBS）. Moreover, it significantly reduced expressions of cleaved IL-lfl, NLRP3 and cleaved Caspase-1 but not ASC in colons of mice. In THP-1 cells, NOR suppressed the expressions of NLRP3, cleaved Caspase-1 and cleaved IL-1β but not ASC induced by lipopolysaccharide （LPS） and adenosine triphosphate （ATP）. Furthermore, NOR could activate aryl hydrocarbon receptor （AhR） in THP-1 cells, inducing CYP1A1 mRNA expression, and promoting dissociation of AhR/HSP90 complexes, association of AhR and ARNT, AhR nuclear translocation, XRE reporter activity and binding activity of AhR/ARNT/XRE. Both siAhR and a-naphthoflavone （a-NF） markedly diminished the inhibition of NOR on NLRP3 inflammasome activation. In addition, NOR elevated Nrf2 level and reduced ROS level in LPS- and ATP-stimulated THP-1 cells, which was reversed by either siAhR or α-NF treatment. Finally, correlations between activation of AhR and attenuation of colitis, inhibition of NLRP3 inflammasome activation and up-regulation of Nrf2 level in colons were validated in mice with TNBS-induced colitis. Taken together, NOR ameliorated TNBS-induced colitis in mice through inhibiting NLRP3 inflammasome activation via regulating AhR/Nrf2/ROS signaling pathway.

The aryl hydrocarbon receptor and the gut–brain axis

The aryl hydrocarbon receptor(AHR)is a ligand-activated transcription factor initially identified as the receptor for dioxin.Almost half a century after its discovery,AHR is now recognized as a receptor for multiple physiological ligands,with important roles in health and disease.In this review,we discuss the role of AHR in the gut–brain axis and its potential value as a therapeutic target for immune-mediated diseases.

Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome

Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

Aryl hydrocarbon receptor signaling promotes ORMDL3- dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase

Aryl hydrocarbon receptor(AhR),a cellular chemical sensor,controls cellular homeostasis,and sphingosine-1-phosphate(S1P),a bioactive intermediate of sphingolipid metabolism,is believed to have a role in immunity and inflammation,but their potential crosstalk is currently unknown.We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism.We showed that AhR ligands,including an environmental polycyclic aromatic hydrocarbon(PAH),induced S1P generation,and inhibited S1P lyase(S1PL)activity in resting cells,antigen/IgE-activated mast cells,and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge.The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317,which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein,whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect.Furthermore,analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex,which was confirmed by FRET analysis.This change increased the S1P levels,which in turn,induced mast cell degranulation via S1PR2 signaling.In addition,elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects.These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL,which may contribute to the expression of allergic diseases.

Interaction between Kynurenine and Aryl Hydrocarbon Receptor in Regulating the Balance of T helper 17 Cells and Regulatory T-cells in Decidua during Early Gestation

Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual naïve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual naïve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.