Role of the aryl hydrocarbon receptor (AhR) in lung inflammation

Beamer, Celine A.; Shepherd, David M.

doi:10.1007/s00281-013-0391-7

Cited by 81 publications

(77 citation statements)

References 121 publications

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“…Important genes include AHR, CD69, FAS, and JUN (Table 4). AHR (arylhydrocarbon receptor) plays an important role in airway inflammation via its effect on bronchial epithelia and immune cells (23). After ligation, the AHR-dioxin complex induces the transcription of detoxification enzymes to detoxify dioxin-like compounds into physiologic metabolites and influence immune responsiveness and mucosal barrier function of epithelium in the lung.…”

Section: Resultsmentioning

confidence: 99%

RNA Seq profiling reveals a novel expression pattern of TGF-β target genes in human blood eosinophils

Esnault

Dozmorov

et al. 2015

Immunology Letters

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Despite major advances in our understanding of TGF-β signaling in multiple cell types, little is known about the direct target genes of this pathway in human eosinophils. These cells constitute the major inflammatory component present in the sputum and lung of active asthmatics and their numbers correlate well with disease severity. During the transition from acute to chronic asthma, TGF-β levels rise several fold in the lung which drives fibroblasts to produce extracellular matrix (ECM) and participate in airway and parenchymal remodeling. In this report, we use purified blood eosinophils from healthy donors and analyze baseline and TGF-β responsive genes by RNA Seq, and demonstrate that eosinophils (PBE) express 7,981 protein-coding genes of which 178 genes are up-regulated and 199 genes are down-regulated by TGF-β. While 18 target genes have been previously associated with asthma and eosinophilic disorders, the vast majority have been implicated in cell death and survival, differentiation, and cellular function. Ingenuity pathway analysis revealed that 126 canonical pathways are activated by TGF-β including iNOS, TREM1, p53, IL-8 and IL-10 signaling. As TGF-β is an important cytokine for eosinophil function and survival, and pulmonary inflammation and fibrosis, our results represent a significant step toward the identification of novel TGF-β responsive genes and provide a potential therapeutic opportunity by selectively targeting relevant genes and pathways.

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Section: Resultsmentioning

confidence: 99%

RNA Seq profiling reveals a novel expression pattern of TGF-β target genes in human blood eosinophils

Esnault

Dozmorov

et al. 2015

Immunology Letters

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“…10,39,40 In these models, AhR activation led to reduced eosinophilia, inhibited Th2 and challenged with OVA as described, and total and OVA-specific IgE and IgG1 was measured in serum as described. 31 (a) Total IgE,…”

Section: Discussionmentioning

confidence: 99%

“…cytokine and IgE production, increased Th1 cytokine levels, and decreased expression of the Th2 transcription factor GATA3. 10,39,40 However, these studies did not investigate whether the AhR ligands were acting directly on T cells or on accessory cells that may programme the T-cell responses. Our lymph node antigen recall experiments showed that T-cell activation in AhR À/À lymph node cells was significantly stronger than was seen in controls, with greater antigen-specific proliferation and cytokine production (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In rodent models of asthma-like disease using ovalbumin (OVA) or house dust mite, TCDD reduces eosinophilia, cytokine production and IgE levels. [7][8][9][10] Evidence suggests that the AhR regulates the balance of immunosuppressive regulatory T lymphocytes and effector T helper type 2 (Th2) and Th17 cells. For example, TCDD promotes the expansion of regulatory T cells and inhibits activation of helper and cytotoxic T cells.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

“…13,14 In the context of allergic hypersensitivity, AhR agonists inhibit Th2-mediated cytokine production and allergic responses in mouse models of atopic dermatitis, food allergy and asthma-like disease. 10,15,16 However, when using whole animal models, it is difficult to determine whether the effects of AhR ligands are due to direct effects on T cells or to effects on T-cell programming by antigen-presenting cells. Interestingly, wild-type recipients of adoptively transferred AhR-deficient T cells displayed TCDD-induced inhibition of T-cell proliferation in response to influenza virus, 11,17 suggesting that antigenpresenting cells play a key a role in AhR modulation of T-cell function.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

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Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function

et al. 2015

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Summary The aryl hydrocarbon receptor (AhR) is a transcription factor that has been extensively studied as a regulator of toxicant metabolism. However, recent evidence indicates that the AhR also plays an important role in immunity. We hypothesized that the AhR is a novel, immune regulator of T helper type 2 (Th2) ‐mediated allergic airway disease. Here, we report that AhR‐deficient mice develop increased allergic responses to the model allergen ovalbumin (OVA), which are driven in part by increased dendritic cell (DC) functional activation. AhR knockout (AhR−/−) mice sensitized and challenged with OVA develop an increased inflammatory response in the lung compared with wild‐type controls, with greater numbers of inflammatory eosinophils and neutrophils, greater T‐cell proliferation, greater production of Th2 cytokines, and higher levels of OVA‐specific IgE and IgG1. Lung DCs from AhR−/− mice stimulated antigen‐specific proliferation and Th2 cytokine production by naive T cells in vitro. Additionally, AhR−/− DCs produced higher levels of tumour necrosis factor‐α and interleukin‐6, which promote Th2 differentiation, and expressed higher cell surface levels of stimulatory MHC Class II and CD86 molecules. Overall, loss of the AhR was associated with enhanced T‐cell activation by pulmonary DCs and heightened pro‐inflammatory allergic responses. This suggests that endogenous AhR ligands are involved in the normal regulation of Th2‐mediated immunity in the lung via a DC‐dependent mechanism. Therefore, the AhR may represent an important target for therapeutic intervention in allergic airways inflammation.

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Metformin inhibits IgE‐ and aryl hydrocarbon receptor‐mediated mast cell activation in vitro and in vivo

Wang

Huang

2018

Eur J Immunol

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Metformin, an anti-diabetic drug, possesses anti-inflammatory property beyond its glucose-lowering activity, but its regulatory effect on mast cells and allergic responses remains unknown, wherein the aryl hydrocarbon receptor (AhR)-ligand axis is critical in controlling mast cell activation. Herein, we provide evidence supporting the role of metformin in modulating mast cell activation by FcεR1-, AhR-mediated signaling or their combination. Metformin at relatively low doses was shown to suppress FcεR1mediated degranulation, IL-13, TNF-α and sphingosine-1-phosphate (S1P) secretion in murine bone marrow-derived mast cells (BMMCs). In contrast, metformin at the same doses potently inhibited all parameters in mast cells stimulated with an AhR ligand, 5,11dihydroindolo[3,2-b]carbazole-6-carbaldehyde (FICZ). Further, metformin was shown to inhibit FcεR1-and AhR-mediated passive cutaneous anaphylaxis (PCA) in vivo, reversible by a S1P receptor 2 antagonist, JTE-013. Using AhR reporter cells, Huh7-DRE-Luc cells, a human mast cell line, HMC-1, and BMMCs, metformin's inhibitory effect was mediated through the suppression of FICZ-induced AhR activity, calcium mobilization and ROS generation. Notably, FICZ-mediated oxidation of S1P lyase (S1PL) and its reduced activity were reversed by metformin, resulting in decreased levels of S1P. Collectively, these results suggested the potential utility of metformin in treating allergic diseases, particularly in cases with comorbid type II diabetes mellitus.Keywords: Aryl hydrocarbon receptor r Mast cell r Metformin r Sphingosine-1-phosphate r Sphingosine-1-phosphate lyase Additional supporting information may be found online in the Supporting Information section at the end of the article. Abbreviations: AhR: aryl hydrocarbon receptor · FICZ: 5,11dihydroindolo[3,2-b]carbazole-6-carbaldehyde · Met: metformin · S1P: sphingosine-1-phosphate · S1PL: sphingosine-1-phosphate lyase

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Role of the aryl hydrocarbon receptor (AhR) in lung inflammation

Cited by 81 publications

References 121 publications

RNA Seq profiling reveals a novel expression pattern of TGF-β target genes in human blood eosinophils

RNA Seq profiling reveals a novel expression pattern of TGF-β target genes in human blood eosinophils

Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function

Metformin inhibits IgE‐ and aryl hydrocarbon receptor‐mediated mast cell activation in vitro and in vivo

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