title: Double-stranded RNA exacerbates pulmonary allergic reaction through TLR3: implication of airway epithelium and dendritic cells.
abstract: Respiratory viral infections have been implicated in exacerbations of allergic asthma, characterized by a Th2-biased immune response. Respiratory viruses target airway epithelial cells and dendritic cells (DCs). Their activation is, at least in part, mediated by the TLR3-dependent recognition of virus-derived dsRNA. To elucidate the role of epithelial cells and DCs and the implication of TLR3/Toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) pathway, we developed a mouse model of lung allergic exacerbation. The effect of intranasal administration of dsRNA in OVA-sensitized wild-type mice and TRIF(-/-) mice was evaluated on airway hyperresponsiveness and pulmonary inflammation. Our data demonstrated that treatment with dsRNA significantly increased the airway hyperresponsiveness, the lung inflammation, and the OVA-specific Th2 response. This was associated with an infiltrate of eosinophils, myeloid DCs, and T lymphocytes. TRIF activation was required for the development of dsRNA-induced exacerbation of the allergic reaction. Intratracheal transfer of IL-4/dsRNA/OVA-pretreated DCs also triggered exacerbation of the allergic reaction, whereas cells primed with dsRNA/OVA had a more limited effect. dsRNA-induced production of CCL20 by airway epithelium was associated with DC recruitment. In vivo and in vitro treatment with dsRNA amplified airway epithelial production of the pro-Th2 chemokines CCL11 and CCL17, their secretion being enhanced by Th2 cytokines. In conclusion, dsRNA derived from respiratory viruses trigger exacerbation of the pulmonary allergic reaction through TLR3/TRIF-dependent pathway. Moreover, Th2 cytokines participate in this process by modulating the response of airway epithelium and DCs to dsRNA.
authors.affiliation: Infection Pulmonaire et Immunité Innée, Institut National de la Santé et de la Recherche Médicale, Unité 1019, France.
authors.forename: David
authors.initials: D
authors.lastname: Torres
authors.forename: Audrey
authors.initials: A
authors.lastname: Dieudonné
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Eva
authors.initials: E
authors.lastname: Vilain
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.forename: Muriel
authors.initials: M
authors.lastname: Pichavant
authors.forename: Philippe
authors.initials: P
authors.lastname: Lassalle
authors.forename: François
authors.initials: F
authors.lastname: Trottein
authors.forename: Philippe
authors.initials: P
authors.lastname: Gosset
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000485:Allergens / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000633:toxicity*; D012367:RNA, Viral / Q000008:administration & dosage / Q000633:toxicity*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000485:Allergens; D010047:Ovalbumin; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse