A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles
Publikation: Beitrag in Fachzeitschrift › Forschungsartikel › Beigetragen › Begutachtung
Beitragende
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.
Details
Originalsprache | Englisch |
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Seiten (von - bis) | 1243-1256.e17 |
Fachzeitschrift | Journal of Allergy and Clinical Immunology |
Jahrgang | 142 |
Ausgabenummer | 4 |
Publikationsstatus | Veröffentlicht - Okt. 2018 |
Peer-Review-Status | Ja |
Extern publiziert | Ja |
Externe IDs
PubMedCentral | PMC6173656 |
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Scopus | 85046691406 |
Schlagworte
Schlagwörter
- Air Pollutants/toxicity, Animals, Antibodies, Monoclonal/therapeutic use, Antigen-Presenting Cells/immunology, Immunoglobulin G/immunology, Jagged-1 Protein/immunology, Macrophages, Alveolar/immunology, Mice, Inbred BALB C, Mice, Transgenic, Particulate Matter/toxicity, Receptor, Notch4/antagonists & inhibitors, Respiratory Hypersensitivity/drug therapy, T-Lymphocytes/immunology