Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Department of Civil and Environmental Engineering, University of Southern California, Los Angeles, Calif.
J Allergy Clin Immunol. 2018 Oct;142(4):1243-1256.e17. doi: 10.1016/j.jaci.2018.03.009. Epub 2018 Apr 5.
Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear.
We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP).
We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies.
We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted T2 and T17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4-dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP.
UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented T cell differentiation.
接触与交通相关的颗粒物会促进哮喘和过敏性疾病。然而，颗粒物暴露介导这些效应的确切细胞和分子机制仍不清楚。
我们旨在阐明环境超细颗粒物（UFP）增强过敏性气道炎症所必需的细胞靶标和信号通路。
我们使用体外肺源性抗原呈递细胞和过敏原特异性 T 细胞培养试验以及髓系特异性基因缺失、细胞重建方法和抗体抑制研究的过敏性气道炎症小鼠模型。
我们发现肺泡巨噬细胞（AM）是 UFP 促进气道炎症的关键细胞靶标。UFP 通过依赖于芳烃受体的Jag1（Jag1）表达诱导在 AM 中是增强 UFP 诱导的过敏性气道炎症所必需和充分的。UFP 以 Jag1 和 Notch4 依赖性方式促进过敏原特异性 T 细胞的 T2 和 T17 细胞分化。用抗 Notch4 抗体治疗可消除 UFP 诱导的过敏性气道炎症加重。
UFP 通过促进 AM 和过敏原特异性 T 细胞之间的 Jag1-Notch4 依赖性相互作用，促进 T 细胞分化，从而加重过敏性气道炎症。
