Assuntos
Receptores de Hidrocarboneto Arílico , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Humanos , Animais , Interferons/imunologia , Interferons/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Camundongos , Transdução de Sinais/imunologiaRESUMO
Background: Allergen-specific immunotherapy (AIT) is able to restore immune tolerance to allergens in allergic patients. However, some patients do not or only poorly respond to current treatment protocols. Therefore, there is a need for deeper mechanistic insights and further improvement of treatment strategies. The relevance of the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, has been investigated in several inflammatory diseases, including allergic asthma. However, its potential role in AIT still needs to be addressed. Methods: A murine model of AIT in ovalbumin-induced allergic airway inflammation was performed in AhR-deficient (AhR-/-) and wild-type mice. Furthermore, AIT was combined with the application of the high-affinity AhR agonist 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ) as an adjuvant to investigate the effects of AhR activation on therapeutic outcome. Results: Although AhR-/- mice suffer stronger allergic responses than wild-type mice, experimental AIT is comparably effective in both. Nevertheless, combining AIT with the administration of 10-Cl-BBQ improved therapeutic effects by an AhR-dependent mechanism, resulting in decreased cell counts in the bronchoalveolar fluid, decreased pulmonary Th2 and Th17 cell levels, and lower sIgE levels. Conclusion: This study demonstrates that the success of AIT is not dependent on the AhR. However, targeting the AhR during AIT can help to dampen inflammation and improve tolerogenic vaccination. Therefore, AhR ligands might represent promising candidates as immunomodulators to enhance the efficacy of AIT.
Assuntos
Adjuvantes Imunológicos , Alérgenos , Asma , Dessensibilização Imunológica , Modelos Animais de Doenças , Camundongos Knockout , Receptores de Hidrocarboneto Arílico , Animais , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/agonistas , Camundongos , Dessensibilização Imunológica/métodos , Alérgenos/imunologia , Asma/imunologia , Asma/terapia , Ovalbumina/imunologia , Feminino , Camundongos Endogâmicos C57BL , Células Th2/imunologia , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
The aryl hydrocarbon receptor (AhR)-interacting protein (AIP) is a ubiquitously expressed, immunophilin-like protein best known for its role as a co-chaperone in the AhR-AIP-Hsp90 cytoplasmic complex. In addition to regulating AhR and the xenobiotic response, AIP has been linked to various aspects of cancer and immunity that will be the focus of this review article. Loss-of-function AIP mutations are associated with pituitary adenomas, suggesting that AIP acts as a tumor suppressor in the pituitary gland. However, the tumor suppressor mechanisms of AIP remain unclear, and AIP can exert oncogenic functions in other tissues. While global deletion of AIP in mice yields embryonically lethal cardiac malformations, heterozygote, and tissue-specific conditional AIP knockout mice have revealed various physiological roles of AIP. Emerging studies have established the regulatory roles of AIP in both innate and adaptive immunity. AIP interacts with and inhibits the nuclear translocation of the transcription factor IRF7 to inhibit type I interferon production. AIP also interacts with the CARMA1-BCL10-MALT1 complex in T cells to enhance IKK/NF-κB signaling and T cell activation. Taken together, AIP has diverse functions that vary considerably depending on the client protein, the tissue, and the species.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias , Receptores de Hidrocarboneto Arílico , Animais , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Camundongos , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/imunologia , Imunidade InataRESUMO
L. johnsonii N6.2 releases nano-sized vesicles (NVs) with distinct protein and lipid contents. We hypothesized that these NVs play a central role in the delivery of bioactive molecules that may act as mechanistic effectors in immune modulation. In this report, we observed that addition of NVs to the human pancreatic cell line ßlox5 reduced cytokine-induced apoptosis. Through RNAseq analyses, increased expression of CYP1A1, CYP1B1, AHRR, and TIPARP genes in the aryl hydrocarbon receptor (AHR) pathways were found to be significantly induced in presence of NVs. AHR nuclear translocation was confirmed by confocal microscopy. The role of NVs on beta cell function was further evaluated using primary human pancreatic islets. It was found that NVs significantly increased insulin secretion in presence of high glucose concentrations. These increases positively correlated with increased GLUT6 and SREBF1 mRNA and coincided with reduced oxidative stress markers. Furthermore, incubation of NVs with THP-1 macrophages promoted the M2 tolerogenic phenotype through STAT3 activation, expression of AHR-dependent genes and secretion of IL10. Altogether, our findings indicate that bacterial NVs have the potential to modulate glucose homeostasis in the host by directly affecting insulin secretion by islets and through the induction of a tolerogenic immune phenotype.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Interleucina-10 , Lactobacillus johnsonii , Receptores de Hidrocarboneto Arílico , Apoptose/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Glucose/metabolismo , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Lactobacillus johnsonii/genética , Lactobacillus johnsonii/imunologia , Lactobacillus johnsonii/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
T follicular helper (Tfh) cells support Ab responses and are a critical component of adaptive immune responses to respiratory viral infections. Tfh cells are regulated by a network of signaling pathways that are controlled, in part, by transcription factors. The aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that modulates many aspects of adaptive immunity by binding a range of small molecules. However, the contribution of AHR signaling to Tfh cell differentiation and function is not known. In this article, we report that AHR activation by three different agonists reduced the frequency of Tfh cells during primary infection of C57BL/6 mice with influenza A virus (IAV). Further, using the high-affinity and AHR-specific agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin, we show that AHR activation reduced Tfh cell differentiation and T cell-dependent B cell responses. Using conditional AHR knockout mice, we demonstrated that alterations of Tfh cells and T cell-dependent B cell responses after AHR activation required the AHR in T cells. AHR activation reduced the number of T follicular regulatory (Tfr) cells; however, the ratio of Tfr to Tfh cells was amplified. These alterations to Tfh and Tfr cells during IAV infection corresponded with differences in expression of BCL6 and FOXP3 in CD4+ T cells and required the AHR to have a functional DNA-binding domain. Overall, these findings support that the AHR modulates Tfh cells during viral infection, which has broad-reaching consequences for understanding how environmental factors contribute to variation in immune defenses against infectious pathogens, such as influenza and severe acute respiratory syndrome coronavirus.
Assuntos
Vírus da Influenza A , Infecções por Orthomyxoviridae , Células T Auxiliares Foliculares , Animais , Diferenciação Celular , Vírus da Influenza A/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Células T Auxiliares Foliculares/imunologiaRESUMO
The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.
Assuntos
Tolerância Imunológica/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Triptofano/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Humanos , Indóis/imunologia , Indóis/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Microbiota/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/metabolismoRESUMO
Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.
Assuntos
Linfócitos B Reguladores/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Diferenciação Celular/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Pulmonar de Lewis/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismoRESUMO
Background: Despite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations. Objectives: We sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma. Methods: Cockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated. Results: Cockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1ß), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1ß generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs. Conclusions: These results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.
Assuntos
Asma/imunologia , Células Epiteliais/imunologia , Inflamassomos/imunologia , Mucina-5AC/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espécies Reativas de Oxigênio/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Alérgenos/imunologia , Animais , Asma/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-5AC/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcript factor that plays an important role in regulating immunity and cell differentiation. However, its role in cell-autonomous antiviral resistance has not been fully elucidated. Here, we show that interruption of AHR signaling in human cells by a chemical antagonist or genetic targeting led to significant reductions in the replication of herpes simplex virus 1 (HSV-1) and cytomegalovirus (CMV), revealing an unexpected proviral function of AHR. Interestingly, the enhanced viral control in the absence of AHR is independent of type I interferon (IFN) signaling. Together, these results reveal a previously unknown function of AHR in promoting viral replication in vitro and suggest a potential intervention point for treating viral disease. IMPORTANCE This study describes how a virus might utilize host aryl hydrocarbon receptor signaling to promote its replication, even in the presence of type I interferons.
Assuntos
Herpes Simples/imunologia , Herpesvirus Humano 1/fisiologia , Interferon Tipo I/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Herpes Simples/genética , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Humanos , Interferon Tipo I/genética , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Replicação ViralRESUMO
The prevalence of chronic inflammatory diseases including inflammatory bowel disease (IBD), autoimmunity and cancer have increased in recent years. Herbal-based compounds such as flavonoids have been demonstrated to contribute to the modulation of these diseases although understanding their mechanism of action remains limited. Flavonoids are able to interact with cellular immune components in a distinct way and influence immune responses at a molecular level. In this mini review, we highlight recent progress in our understanding of the modulation of immune responses by the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor whose activity can be regulated by diverse molecules including flavonoids. We focus on the role of AhR in integrating signals from flavonoids to modulate inflammatory responses using in vitro and experimental animal models. We also summarize the limitations of these studies. Medicinal herbs have been widely used to treat inflammatory disorders and may offer a valuable therapeutic strategy to treat aberrant inflammatory responses by modulation of the AhR pathway.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Imunomodulação , Fitoterapia , Plantas Medicinais/química , Receptores de Hidrocarboneto Arílico/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Flavonoides/química , Flavonoides/imunologia , Flavonoides/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ligantes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Background: Previous studies have reported the potential of aryl hydrocarbon receptor (AhR) in cancer immunotherapy. However, the mechanisms underpinning its therapeutic value have yet to be comprehensively investigated. Thus, this research aimed to explore the underlying association between AhR and cancer immunotherapy in 33 human cancers. Methods: The gene expression data and clinical characteristics of 33 cancers were retrieved from The Cancer Genome Atlas database. The immunotherapeutic cohorts included GSE67501 and GSE78220 as well as IMvigor210, which were obtained from the Gene Expression Omnibus database and included in a previously published study respectively. Clinical parameters, including patient age, gender, survival, and tumor stage were analyzed to assess the prognostic value of AhR. The activity of AhR was generated by single sample gene set enrichment analysis and used to evaluate the difference between the AhR transcriptome and protein expression level. To better understand the role of AhR in cancer immunotherapy, the correlation between AhR and tumor microenvironment, as well as its relation to immune processes/elements, such as immune cell infiltration, immune inhibitors and stimulators, and the major histocompatibility complex were analyzed. The relevant underlying pathways associated with AhR signaling in cancer were also explored. Furthermore, the correlation between AhR and two immunotherapeutic biomarkers (tumor mutational burden and microsatellite instability) was investigated. Finally, the relationship between AhR and immunotherapeutic response was explored using three independent immunotherapeutic cohorts. Results: Although AhR was not closely associated with age (5/33), gender (3/33), or tumor stage (3/21) in any of the studied human cancers, it exhibited potential prognostic value for predicting patient survival. Consistency has been observed between AhR activity and expression in some cancers (7/33). Generally, AhR presented a robust correlation with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high AhR expression was significantly related to immune-relevant pathways. However, no significant correlation was observed between AhR and the immunotherapeutic response. Conclusions: This research investigated the immunotherapeutic value of AhR in 33 human cancers, providing evidence regarding the function of AhR and its role in clinical treatment. However, considering that a bioinformatics approach was adopted, the current results are preliminary and require further validation.
Assuntos
Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/genética , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Instabilidade de Microssatélites , Neoplasias/classificação , Neoplasias/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transcriptoma , Microambiente Tumoral/imunologiaRESUMO
Accumulating evidence indicates that nutrition can modulate the immune system through metabolites, either produced by host digestion or by microbiota metabolism. In this review, we focus on dietary metabolites that are agonists of the Aryl hydrocarbon Receptor (AhR). AhR is a ligand-activated transcription factor, initially characterized for its interaction with xenobiotic pollutants. Numerous studies have shown that AhR also recognizes indoles and tryptophan catabolites originating from dietary compounds and commensal bacteria. Here, we review recent work employing diet manipulation to address the impact of nutritional AhR agonists on immune responses, both locally in the intestine and at distant sites. In particular, we examine the physiological role of these metabolites in immune cell development and functions (including T lymphocytes, innate-like lymphoid cells, and mononuclear phagocytes) and their effect in inflammatory disorders.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Alimentos , Intestinos/imunologia , Fagócitos/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Linfócitos T/imunologia , Humanos , Inflamação/imunologia , LigantesRESUMO
In agreement with other fungal infections, immunoprotection in pulmonary paracoccidioidomycosis (PCM) is mediated by Th1/Th17 cells whereas disease progression by prevalent Th2/Th9 immunity. Treg cells play a dual role, suppressing immunity but also controlling excessive tissue inflammation. Our recent studies have demonstrated that the enzyme indoleamine 2,3 dioxygenase (IDO) and the transcription factor aryl hydrocarbon receptor (AhR) play an important role in the immunoregulation of PCM. To further evaluate the immunomodulatory activity of AhR in this fungal infection, Paracoccidioides brasiliensis infected mice were treated with two different AhR agonists, L-Kynurenin (L-Kyn) or 6-formylindole [3,2-b] carbazole (FICZ), and one AhR specific antagonist (CH223191). The disease severity and immune response of treated and untreated mice were assessed 96 hours and 2 weeks after infection. Some similar effects on host response were shared by FICZ and L-Kyn, such as the reduced fungal loads, decreased numbers of CD11c+ lung myeloid cells expressing activation markers (IA, CD40, CD80, CD86), and early increased expression of IDO and AhR. In contrast, the AhR antagonist CH223191 induced increased fungal loads, increased number of pulmonary CD11c+ leukocytes expressing activation markers, and a reduction in AhR and IDO production. While FICZ treatment promoted large increases in ILC3, L-Kyn and CH223191 significantly reduced this cell population. Each of these AhR ligands induced a characteristic adaptive immunity. The large expansion of FICZ-induced myeloid, lymphoid, and plasmacytoid dendritic cells (DCs) led to the increased expansion of all CD4+ T cell subpopulations (Th1, Th2, Th17, Th22, and Treg), but with a clear predominance of Th17 and Th22 subsets. On the other hand, L-Kyn, that preferentially activated plasmacytoid DCs, reduced Th1/Th22 development but caused a robust expansion of Treg cells. The AhR antagonist CH223191 induced a preferential expansion of myeloid DCs, reduced the number of Th1, Th22, and Treg cells, but increased Th17 differentiation. In conclusion, the present study showed that the pathogen loads and the immune response in pulmonary PCM can be modulated by AhR ligands. However, further studies are needed to define the possible use of these compounds as adjuvant therapy for this fungal infection.
Assuntos
Diferenciação Celular/imunologia , Ligantes , Linfócitos/fisiologia , Paracoccidioidomicose/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Índice de Gravidade de Doença , Animais , Diferenciação Celular/genética , Imunidade Inata , Imunomodulação , Pulmão/imunologia , Pneumopatias Fúngicas/imunologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologiaRESUMO
We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFß1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFß1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFß1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFß1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR-RhoA in regulating TGFß1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.
Assuntos
Antígenos de Dermatophagoides/toxicidade , Proteínas de Artrópodes/toxicidade , Asma , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Benzo(a)pireno/toxicidade , Cisteína Endopeptidases/toxicidade , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/imunologia , Proteína rhoA de Ligação ao GTP/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Feminino , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
OBJECTIVE: To investigate involvement of the aryl hydrocarbon receptor (AhR) in the immunomodulatory effects of cadmium (Cd). METHODS: The effect of Cd on AhR activation ( CYP1A1 and CYP1B1 mRNA 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 AhR signaling in the effects of Cd on the interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF) lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191. RESULTS: Cd increased CYP1B1 ( in vivo and in vitro) and CYP1A1 ( in vitro) mRNA, indicating AhR 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-1ß production due to reduced NLRP3. The AhR antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response. The absence of AhR 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 AhR repressor mRNA level. CONCLUSION: AhR signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd. The relevance of the AhR to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cádmio/toxicidade , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocinas/imunologia , Poluentes Ambientais/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Citocromo P-450 CYP1A1/imunologia , Citocromo P-450 CYP1B1/imunologia , Masculino , Ratos , Receptores de Hidrocarboneto Arílico/imunologiaRESUMO
Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even "paradigmatic", shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor "aryl hydrocarbon receptor" (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Pele/imunologia , Timo/imunologia , Animais , HumanosRESUMO
Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand ("A18") that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Enterocolite Necrosante/genética , Indóis/administração & dosagem , Leite Humano/fisiologia , Receptores de Hidrocarboneto Arílico/genética , Receptor 4 Toll-Like/genética , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/imunologia , Dieta/métodos , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/patologia , Enterocolite Necrosante/prevenção & controle , Feminino , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Ligantes , Exposição Materna , Camundongos , Gravidez , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais , Suínos , Receptor 4 Toll-Like/imunologiaRESUMO
Dendritic cells (DCs) are potent antigen-presenting cells (APCs), which sample the exogenous and endogenous cues to control adaptive immunity, balancing effector and regulatory components of the immune response. Multiple subsets of DCs, such as plasmacytoid and conventional DCs, have been defined based on specific phenotypic markers, functions and regulatory transcriptional programs. Tolerogenic DCs (tolDCs) have been functionally defined based on their ability to expand the regulatory T-cell compartment and suppress immune responses. However, it is still unclear whether tolDCs represent a homogeneous population, a specific DC subset and/or a heterogeneous collection of DC activation/maturation states. The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) has been shown to control transcriptional programs associated to tolDCs. In this review, we discuss the role of AHR in the control of tolDCs, and also AHR-targeted approaches for the therapeutic induction of tolDCs in autoimmune diseases and allergy.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Células Dendríticas/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Doenças Autoimunes/imunologia , Humanos , Hipersensibilidade/imunologia , Transdução de Sinais/imunologiaRESUMO
BACKGROUND: Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are CD4+ T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of CD4+ T cells to remain affected into adulthood remain unclear. OBJECTIVE: Our goal was to identify cellular mechanisms that drive impaired CD4+ T-cell responses later in life following maternal exposure to an exogenous AhR ligand. METHODS: C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in CD4+ T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of CD4+ T cells from developmentally exposed mice to infection. RESULTS: Gene and protein expression showed that developmental AhR activation reduced CD4+ T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the CD4+ T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired CD4+ T-cell responses. DISCUSSION: Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of CD4+ T-cell functional responsiveness. https://doi.org/10.1289/EHP7699.
Assuntos
Linfócitos T CD4-Positivos , Metilação de DNA , Exposição Ambiental , Infecções por Orthomyxoviridae , Dibenzodioxinas Policloradas , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Metilação de DNA/efeitos dos fármacos , Feminino , Vírus da Influenza A/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Dibenzodioxinas Policloradas/toxicidade , Gravidez , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismoRESUMO
OBJECTIVE: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS. METHODS: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes. RESULTS: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia. CONCLUSIONS: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.