Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade

J Allergy Clin Immunol. 2015 Aug;136(2):441-53. doi: 10.1016/j.jaci.2015.02.014. Epub 2015 Mar 29.


Background: Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive.

Objective: We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM.

Methods: We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation.

Results: We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic 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. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM.

Conclusion: PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.

Keywords: Jagged 1; Notch; Traffic-related particulate matter; airway hyperresponsiveness; allergic airway inflammation; aryl hydrocarbon receptor; asthma; diesel exhaust particles; ultrafine particles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Allergens / adverse effects*
  • Animals
  • Bronchial Hyperreactivity / chemically induced
  • Bronchial Hyperreactivity / genetics*
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / pathology
  • CD11c Antigen / genetics
  • CD11c Antigen / immunology
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Disease Models, Animal
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin E / genetics
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / immunology
  • Jagged-1 Protein
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Mice
  • Mice, Transgenic
  • Monocytes / immunology
  • Monocytes / pathology
  • Particulate Matter / adverse effects*
  • Primary Cell Culture
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / immunology
  • Receptors, Aryl Hydrocarbon / genetics*
  • Receptors, Aryl Hydrocarbon / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Respiratory Hypersensitivity / chemically induced
  • Respiratory Hypersensitivity / genetics*
  • Respiratory Hypersensitivity / immunology
  • Respiratory Hypersensitivity / pathology
  • Serrate-Jagged Proteins
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / pathology
  • Vehicle Emissions


  • Allergens
  • CD11c Antigen
  • Calcium-Binding Proteins
  • Il4ra protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH1 protein, human
  • Particulate Matter
  • Receptor, Notch1
  • Receptors, Aryl Hydrocarbon
  • Receptors, Cell Surface
  • Serrate-Jagged Proteins
  • Vehicle Emissions
  • Immunoglobulin E