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

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 2; pp. 441 - 453
• Main Authors: Xia, Mingcan, Viera-Hutchins, Loida, Garcia-Lloret, Maria, Noval Rivas, Magali, Wise, Petra, McGhee, Sean A., Chatila, Zena K., Daher, Nancy, Sioutas, Constantinos, Chatila, Talal A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015; Elsevier Limited
• Subjects: airway hyperresponsiveness; Alleles; Allergens - adverse effects; allergic airway inflammation; Allergy and Immunology; Animals; Antigens; Aqueous solutions; aryl hydrocarbon receptor; Asthma; Atherosclerosis; Atoms & subatomic particles; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - genetics; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - pathology; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - immunology; CD11c Antigen - genetics; CD11c Antigen - immunology; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; diesel exhaust particles; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Humans; Hydrocarbons; Immunoglobulin E - genetics; Inflammation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Jagged 1; Jagged-1 Protein; Lymphocytes; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Transgenic; Monocytes - immunology; Monocytes - pathology; Notch; Particulate Matter - adverse effects; Pollutants; 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; Traffic; Traffic-related particulate matter; ultrafine particles; Vehicle Emissions; PAS; DLL; DMSO; FP; Notch1c; allergic airway inflammation; aryl hydrocarbon receptor; diesel exhaust particles; BMDC; Jagged 1; FICZ; GSI; WT; UFP; CB; airway hyperresponsiveness; Jag1; Notch; asthma; AhR; DEP; Traffic-related particulate matter; ultrafine particles; PAH; OVA; PM; TLR4; DC; Periodic acid–Schiff; Polycyclic aryl hydrocarbon; Gamma-secretase inhibitor; Toll-like receptor; Carbon black particles; Dendritic cell; Ovalbumin; Notch1 intracellular domain; Bone marrow–derived dendritic cell; Wild-type; Delta-like ligand; Fine particles; Particulate matter; Dimethyl sulfoxide; 6-Formylindolo (3,2-b) carbazole
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.02.014

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. We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM. We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation. 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. PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.