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Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

ABSTRACT: Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive.We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM.We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation.We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM.PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.

SUBMITTER: Xia M

PROVIDER: S-EPMC4530027 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

Xia Mingcan M Viera-Hutchins Loida L Garcia-Lloret Maria M Noval Rivas Magali M Wise Petra P McGhee Sean A SA Chatila Zena K ZK Daher Nancy N Sioutas Constantinos C Chatila Talal A TA

The Journal of allergy and clinical immunology 20150329 2

<h4>Background</h4>Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive.<h4>Objective</h4>We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM.<h4>Methods</h4>We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine mode ...[more]

PMID: 25825216

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Project description:Exposure to diesel exhaust particles (DEPs) affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM) on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM), dichloromethane (DCM-EOM), methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1) using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE). By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE). Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR) non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction extracted by DCM also caused an AhR-dependent reduction in global membrane order, which appeared to be connected to the [Ca2+]i increase.

Project description:RationaleAryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined.ObjectivesWe sought to determine whether AhR specifically in type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms.MethodsThe role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knockout mice in AT2 cells (Sftpc-Cre;AhRf/f ). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA sequencing (RNA-seq) analysis.ResultsSftpc-Cre;AhRf/f mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre;AhRf/f mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-β1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy with autophagy inhibitor chloroquine significantly suppressed cockroach allergen-induced airway inflammation, Th2 cytokines in BALFs, and expression of autophagy-related genes LC3 and Atg5 in the lung tissues. In addition, RNA-seq analysis suggests that autophagy is one of the major pathways and that CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that may contribute to the AhR-mediated cockroach allergen-induced airway inflammation and, subsequently, allergic asthma.ConclusionThese results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

Project description:Rationale: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined. Objectives: We sought to determine whether AhR specifically in Type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms. Methods: The role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knock out mice in AT2 cells (Sftpc-Cre;AhRflox/flox). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA-seq analysis. Results: Sftpc-Cre; AhRflox/flox mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 and airway epithelial-derived cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre; AhRflox/flox mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-β1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy suppressed allergic airway inflammation with decreased Th2 and epithelial cell-derived cytokines in BALFs. Additionally, RNA-seq analysis suggests that autophagy is one of the major pathways and CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that contribute to the AhR-mediated allergic airway inflammation. Conclusion: These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

Project description:The generation of oxidative stress by ambient air pollution particles contributes to the development of allergic sensitization and asthma, as demonstrated by intranasal challenge with well-characterized diesel exhaust particle (DEP) suspensions in humans. This effect is due to the presence of redox active organic chemicals in DEP, and can be suppressed by antioxidants and inducers of phase II enzymes in animals. In this communication, we determined whether the administration of a standardized broccoli sprout extract (BSE), which contains a reproducible amount of the sulforaphane (SFN) precursor, glucoraphanin, could be used to suppress the nasal inflammatory response in human subjects challenged with 300 μg of an aqueous DEP suspension (equivalent to daily PM exposure levels on a Los Angeles freeway). SFN is capable of inducing an antioxidant and phase II response via activation of the nuclear transcription factor (erythroid-derived 2)-like 2 (Nrf2). Previous studies have shown that 70-90% SFN delivered by BSE is absorbed, metabolized, and excreted in humans. An initial intranasal challenge with DEP in 29 human subjects was used to characterize the magnitude of the inflammatory response. Following a 4 week washout, a BSE that delivers a reproducible and standardized dose of 100 μmol SFN in mango juice was administered daily for four days. The nasal DEP challenge was repeated and lavage fluid collected to perform white blood cell (WBC) counts. The average nasal WBC increased by 66% over the initial screening levels and by 85% over the control levels 24 hours after DEP exposure. However, total cell counts decreased by 54% when DEP challenge was preceded by daily BSE administration for 4 days (p < 0.001). Since the SFN dose in these studies is equivalent to the consumption of 100-200 g broccoli, our study demonstrates the potential preventive and therapeutic potential of broccoli or broccoli sprouts rich in glucoraphanin for reducing the impact of particulate pollution on allergic disease and asthma.

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Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

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Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.

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