Mingcan Xia1, Loida Viera-Hutchins2, Maria Garcia-Lloret2, Magali Noval Rivas1, Petra Wise3, Sean A McGhee4, Zena K Chatila1, Nancy Daher5, Constantinos Sioutas5, Talal A Chatila6. 1. Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. 2. 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. 3. Department of Hematology/Oncology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles, Calif. 4. Division of Immunology & Allergy, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. 5. Department of Civil and Environmental Engineering, University of Southern California, Los Angeles, Calif. 6. Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: talal.chatila@childrens.harvard.edu.
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. CONCLUSION: PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.
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.
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