A Jagged 1–Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles - 05/10/18
Abstract |
Background |
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.
Objective |
We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP).
Methods |
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.
Results |
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 TH2 and TH17 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.
Conclusion |
UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4–dependent interaction between AM and allergen-specific T cells, leading to augmented TH cell differentiation.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Airway hyperresponsiveness, allergic airway inflammation, alveolar macrophages, aryl hydrocarbon receptor, asthma, Jagged 1, Notch, Notch 4, traffic-related particulate matter, ultrafine particles
Abbreviations used : AhR, AM, APC, BAL, Ct, DC, EGFP, Egr2, FACS, Foxp3, FP, IM, iTreg, Jag1, OVA, PAH, PAS, PE, PerCP, PM, Treg, UFP, YG
Plan
| Supported by National Institutes of Health grants 2R01AI065617 and R01AI115699 (to T.A.C.). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 4
P. 1243 - octobre 2018 Retour au numéro
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