title: Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.
abstract: 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.
  
  
  CONCLUSIONS
  PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Mingcan
authors.initials: M
authors.lastname: Xia
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, Calif.
authors.forename: Loida
authors.initials: L
authors.lastname: Viera-Hutchins
authors.affiliation: Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, Calif.
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Lloret
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Magali
authors.initials: M
authors.lastname: Noval Rivas
authors.affiliation: Department of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, Calif.
authors.forename: Petra
authors.initials: P
authors.lastname: Wise
authors.affiliation: Division of Immunology & Allergy, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Sean A
authors.initials: SA
authors.lastname: McGhee
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Zena K
authors.initials: ZK
authors.lastname: Chatila
authors.affiliation: Department of Civil and Environmental Engineering, University of Southern California, Los Angeles, Calif.
authors.forename: Nancy
authors.initials: N
authors.lastname: Daher
authors.affiliation: Department of Civil and Environmental Engineering, University of Southern California, Los Angeles, Calif.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Sioutas
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: talal.chatila@childrens.harvard.edu.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D000483:Alleles; D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D052638:Particulate Matter / Q000009:adverse effects*; D061251:Primary Cell Culture; D051881:Receptor, Notch1 / Q000235:genetics* / Q000276:immunology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology; D001335:Vehicle Emissions; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D000485:Allergens; D039521:CD11c Antigen; D002135:Calcium-Binding Proteins; D007073:Immunoglobulin E; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D052638:Particulate Matter; D051881:Receptor, Notch1; D018336:Receptors, Aryl Hydrocarbon; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D001335:Vehicle Emissions; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497761:NOTCH1 protein, human
keywords: Jagged 1; Notch; Traffic-related particulate matter; airway hyperresponsiveness; allergic airway inflammation; aryl hydrocarbon receptor; asthma; diesel exhaust particles; ultrafine particles
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