title: Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation.
abstract: We have shown that proteinase-activated receptor-2 (PAR(2)) activation in the airways leads to allergic sensitization to concomitantly inhaled Ags, thus implicating PAR(2) in the pathogenesis of asthma. Many aeroallergens with proteinase activity activate PAR(2). To study the role of PAR(2) in allergic sensitization to aeroallergens, we developed a murine model of mucosal sensitization to cockroach proteins. We hypothesized that PAR(2) activation in the airways by natural allergens with serine proteinase activity plays an important role in allergic sensitization. Cockroach extract (CE) was administered to BALB/c mice intranasally on five consecutive days (sensitization phase) and a week later for four more days (challenge phase). Airway hyperresponsiveness (AHR) and allergic airway inflammation were assessed after the last challenge. To study the role of PAR(2), mice were exposed intranasally to a receptor-blocking anti-PAR(2) Ab before each administration of CE during the sensitization phase. Mucosal exposure to CE induced eosinophilic airway inflammation, AHR, and cockroach-specific IgG1. Heat-inactivated or soybean trypsin inhibitor-treated CE failed to induce these effects, indicating that proteinase activity plays an important role. The use of an anti-PAR(2) blocking Ab during the sensitization phase completely inhibited airway inflammation and also decreased AHR and the production of cockroach-specific IgG1. PAR(2) activation by CE acts as an adjuvant for allergic sensitization even in the absence of functional TLR4. We conclude that CE induces PAR(2)-dependent allergic airway sensitization in a mouse model of allergic airway inflammation. PAR(2) activation may be a general mechanism used by aeroallergens to induce allergic sensitization.
authors.affiliation: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Narcy G
authors.initials: NG
authors.lastname: Arizmendi
authors.forename: Melanie
authors.initials: M
authors.lastname: Abel
authors.forename: Koichiro
authors.initials: K
authors.lastname: Mihara
authors.forename: Courtney
authors.initials: C
authors.lastname: Davidson
authors.forename: Danny
authors.initials: D
authors.lastname: Polley
authors.forename: Ahmed
authors.initials: A
authors.lastname: Nadeem
authors.forename: Tamer
authors.initials: T
authors.lastname: El Mays
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Gilmore
authors.forename: Brian
authors.initials: B
authors.lastname: Walker
authors.forename: John R
authors.initials: JR
authors.lastname: Gordon
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Harissios
authors.initials: H
authors.lastname: Vliagoftis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology; D000281:Administration, Intranasal; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D020048:Blattellidae / Q000201:enzymology / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051381:Rats; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D044464:Receptor, PAR-2