Aryl hydrocarbon receptor–ligand axis mediates pulmonary fibroblast migration and differentiation through increased arachidonic acid metabolism

Su, Hsiang Han; Lin, Hsin Ting; Suen, Jau‐Ling; Sheu, Chau‐Chyun; Yokoyama, Kazunari K.; Huang, Shau Ku; Cheng, Chih Mei

doi:10.1016/j.tox.2016.09.019

Cited by 24 publications

(12 citation statements)

References 42 publications

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“…These cell types might also participate in the development of PM2.5/PAH-enhanced allergic inflammation in the airways. 9,[39][40][41][42][43] Indeed, the effects of PM2.5 in promoting an imbalanced response of T H 1/T H 2 cells, 44,45 induction of the inflammasome, 44 and impaired function of Treg cells 18,46 have been noted. Also, previously, we reported that exposure to AhR ligands resulted in enhanced activation of mast cells and the anaphylactic response in vivo.…”

Section: Discussionmentioning

confidence: 99%

Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Sun

Lin

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 mm or less in diameter (PM2.5) aggravates asthma. Objective: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. Methods: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4 1 T cellspecific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of T H 17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. Results: PM2.5 impaired differentiation of Treg cells, promoted differentiation of T H 17 cells, and aggravated asthma in an AhRdependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of T H 17 cells by upregulating hypoxia-inducible factor 1a expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of T H 17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on T H 17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. Conclusions: The AhR-hypoxia-inducible factor 1a and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of T H 17/Treg cells.

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Section: Discussionmentioning

confidence: 99%

Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Sun

Lin

et al. 2020

Journal of Allergy and Clinical Immunology

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“…Activation of the AHR in epithelial cells led to morphological changes associated with cytoskeletal remodeling, increased interaction with the extracellular matrix, and reduced cell-cell contacts (87). AHR activation in lung fibroblasts significantly enhanced migration via generation of arachidonic acid metabolites (88). AHR agonists also significantly increased migration of squamous cell carcinoma cells in culture (89).…”

Section: Discussionmentioning

confidence: 99%

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

et al. 2020

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Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD + ). As a precursor for NAD + , Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD + levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD + serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD + -dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine Moffett et al.Quinolinate as Kynurenine Marker and NAD + Source metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD + synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

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“…The potential of PP2 to inhibit the increase in pulmonary microvascular leakage was also reported implying its action as a potent downregulator of endothelial hyperpermeability [57]. Furthermore, studies revealed that CH223191 also could inhibit migration of cells in response to TCDD-activated AhR in [58]. To further support our findings, we carried out flux FITC-labeled dextran tracer assay and measured the endothelial permeability, which revealed similar phenomena with the result found in TEER (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

Assefa

Yan

Gezahegn

et al. 2019

Oxidative Medicine and Cellular Longevity

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Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

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Aryl hydrocarbon receptor–ligand axis mediates pulmonary fibroblast migration and differentiation through increased arachidonic acid metabolism

Cited by 24 publications

References 42 publications

Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Particulate matter of 2.5 μm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

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