A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles.

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.

• Authors: Mingcan Xia, Hani Harb, Arian Saffari, Constantinos Sioutas, Talal A Chatila
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 142 Issue 4 Pg. 1243-1256.e17 (10 2018) ISSN: 1097-6825 [Electronic] United States
• PMID: 29627423 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Air Pollutants
• Antibodies, Monoclonal
• Immunoglobulin G
• Jagged-1 Protein
• Particulate Matter
• Receptor, Notch4
• Notch4 protein, mouse

Topics

• 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, immunology)
• Respiratory Hypersensitivity (drug therapy, immunology)
• T-Lymphocytes (immunology)