Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.
Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.
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DOI：
10.1016/j.jaci.2015.02.014
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Chatila TA
中科院分区：
文献类型：
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作者：
Xia M;Viera-Hutchins L;Garcia-Lloret M;Noval Rivas M;Wise P;McGhee SA;Chatila ZK;Daher N;Sioutas C;Chatila TA
与交通相关的颗粒物 (PM) 与哮喘和过敏性疾病的发病率升高有关。然而，PM 暴露促进过敏性疾病的分子机制仍不清楚。我们试图确定 PM 促进过敏性气道炎症相关途径的表达、功能和调节。我们采用了过敏性气道炎症的基因表达转录谱、体外培养测定和体内小鼠模型。我们确定了 Notch 通路的基因，尤其是 Jagged 1 (Jag1)，作为人类单核细胞和鼠树突状细胞 (DC) 中 PM 诱导的靶标。 PM，尤其是超细颗粒 (UFP)，以 Jag1 和 Notch 依赖性方式上调小鼠 T 辅助细胞因子、IgE 产生和过敏性气道炎症，特别是在促哮喘 IL-4 受体等位基因 Il4raR576 的背景下。 PM 诱导的 Jag1 表达是由芳烃受体 (AhR) 介导的，该受体与 Jag1 启动子中的 AhR 响应元件结合并激活。 AhR 的药理学拮抗作用或其在 CD11c+ 细胞中的谱系特异性缺失消除了 PM 对气道炎症的增强作用。 PM 激活 AhR-Jag1-Notch 级联，与促哮喘等位基因共同促进过敏性气道炎症。
Traffic-related particulate matter (PM) has been linked to heightened incidence of asthma and allergic diseases. However, molecular mechanisms by which PM exposure promote allergic diseases remain elusive. We sought to determine the expression, function and regulation of pathways involved in the promotion by PM of allergic airway inflammation. We employed gene expression transcriptional profiling, in vitro culture assays, and vivo murine models of allergic airway inflammation. We identified genes of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells (DCs). PM, especially ultrafine particles (UFP), upregulated T helper cytokine, IgE production and allergic airway inflammation in mice in a Jag1 and Notch-dependent manner especially in the context of the pro-asthmatic 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. Pharmacological antagonism of AhR or its lineage-specific deletion in CD11c+ cells abrogated the augmentation of airway inflammation by PM. PM activate an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with pro-asthmatic alleles.