title: Protease-activated receptor-2 activation contributes to house dust mite-induced IgE responses in mice.
abstract: Aeroallergens such as house dust mite (HDM), cockroach, and grass or tree pollen are innocuous substances that can induce allergic sensitization upon inhalation. The serine proteases present in these allergens are thought to activate the protease-activated receptor (PAR)-2, on the airway epithelium, thereby potentially inducing allergic sensitization at the expense of inhalation tolerance. We hypothesized that the proteolytic activity of allergens may play an important factor in the allergenicity to house dust mite and is essential to overcome airway tolerance. Here, we aimed to investigate the role of PAR-2 activation in allergic sensitization and HDM-induced allergic airway inflammation. In our study, Par-2 deficient mice were treated with two different HDM extracts containing high and low serine protease activities twice a week for a period of 5 weeks. We determined airway inflammation through quantification of percentages of mononuclear cells, eosinophils and neutrophils in the bronchial alveolar lavage fluid and measured total IgE and HDM-specific IgE and IgG1 levels in serum. Furthermore, Th2 and pro-inflammatory cytokines including IL-5, IL-13, Eotaxin-1, IL-17, KC, Chemokine (C-C motif) ligand 17 (CCL17) and thymic stromal lymphopoietin (TSLP), were measured in lung tissue homogenates. We observed that independent of the serine protease content, HDM was able to induce elevated levels of eosinophils and neutrophils in the airways of both wild-type (WT) and Par-2 deficient mice. Furthermore, we show that induction of pro-inflammatory cytokines by HDM exposure is independent of Par-2 activation. In contrast, serine protease activity of HDM does contribute to enhanced levels of total IgE, but not HDM-specific IgE. We conclude that, while Par-2 activation contributes to the development of IgE responses, it is largely dispensable for the HDM-induced induction of pro-inflammatory cytokines and airway inflammation in an experimental mouse model of HDM-driven allergic airway disease.
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sijranke
authors.initials: S
authors.lastname: Post
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pulmonology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Arjen H
authors.initials: AH
authors.lastname: Petersen
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Harold G
authors.initials: HG
authors.lastname: de Bruin
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.affiliation: Lab. Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Martijn C
authors.initials: MC
authors.lastname: Nawijn
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D007114:Immunization; D007073:Immunoglobulin E / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D039981:Pyroglyphidae / Q000276:immunology*; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D044464:Receptor, PAR-2; D007073:Immunoglobulin E