Andrea R Teufelberger1, Maria Nordengrün2, Harald Braun3, Tania Maes4, Katrien De Grove4, Gabriele Holtappels5, Clara O'Brien5, Sharen Provoost4, Hamida Hammad6, Amanda Gonçalves7, Rudi Beyaert3, Wim Declercq8, Peter Vandenabeele8, Dmitri V Krysko9, Barbara M Bröker2, Claus Bachert5, Olga Krysko10. 1. Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University, Ghent, Belgium; Molecular Signalling and Cell Death Unit, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. 2. Department of Immunology, University Medicine Greifswald, Greifswald, Germany. 3. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Molecular Signal Transduction in Inflammation Unit, VIB Center for Inflammation Research, Ghent, Belgium. 4. Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University, Ghent, Belgium. 5. Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University, Ghent, Belgium. 6. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium. 7. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB Bio Imaging Core Ghent, VIB Center for Inflammation Research, Ghent, Belgium. 8. Molecular Signalling and Cell Death Unit, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. 9. Department of Basic Medical Sciences, Ghent University, Ghent, Belgium. 10. Upper Airways Research Laboratory, Department of Otorhinolaryngology, Ghent University, Ghent, Belgium. Electronic address: olga.krysko@ugent.be.
Abstract
BACKGROUND: Chronic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps and asthma, show increased nasal Staphylococcus aureus colonization. Staphylococcus aureus-derived serine protease-like protein (Spl) D and other closely related proteases secreted by S aureus have recently been identified as inducers of allergic asthma in human subjects and mice, but their mechanism of action is largely unknown. OBJECTIVE: We investigated the role of recombinant SplD in driving TH2-biased responses and IgE formation in a murine model of allergic asthma. METHODS: Allergic asthma was induced in C57BL/6 J wild-type mice, Toll-like receptor (TLR) 4 knockout (Tlr4-/-) mice, and recombination-activating gene (Rag2) knockout (Rag2-/-) mice by means of repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by means of flow cytometry, ELISA, Luminex, and immunohistochemistry. Serum SplD-specific IgE levels were analyzed by using ELISA. RESULTS: We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity, and goblet cell hyperplasia in the airways. Blocking IL-33 activity with a soluble ST2 receptor significantly decreased the numbers of eosinophils, IL-13+ type 2 innate lymphoid cells and IL-13+CD4+ T cells and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signaling. CONCLUSION: The S aureus-derived protein SplD is a potent allergen of S aureus and induces a TH2-biased inflammatory response in the airways in an IL-33-dependent but TRL4-independent manner. The soluble ST2 receptor could be an efficient strategy to interfere with SplD-induced TH2 inflammation but does not prevent the allergic sensitization.
BACKGROUND: Chronic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps and asthma, show increased nasal Staphylococcus aureus colonization. Staphylococcus aureus-derived serine protease-like protein (Spl) D and other closely related proteases secreted by S aureus have recently been identified as inducers of allergic asthma in human subjects and mice, but their mechanism of action is largely unknown. OBJECTIVE: We investigated the role of recombinant SplD in driving TH2-biased responses and IgE formation in a murine model of allergic asthma. METHODS:Allergic asthma was induced in C57BL/6 J wild-type mice, Toll-like receptor (TLR) 4 knockout (Tlr4-/-) mice, and recombination-activating gene (Rag2) knockout (Rag2-/-) mice by means of repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by means of flow cytometry, ELISA, Luminex, and immunohistochemistry. Serum SplD-specific IgE levels were analyzed by using ELISA. RESULTS: We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity, and goblet cell hyperplasia in the airways. Blocking IL-33 activity with a soluble ST2 receptor significantly decreased the numbers of eosinophils, IL-13+ type 2 innate lymphoid cells and IL-13+CD4+ T cells and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signaling. CONCLUSION: The S aureus-derived protein SplD is a potent allergen of S aureus and induces a TH2-biased inflammatory response in the airways in an IL-33-dependent but TRL4-independent manner. The soluble ST2 receptor could be an efficient strategy to interfere with SplD-induced TH2 inflammation but does not prevent the allergic sensitization.
Authors: Noriko Ogasawara; Aiko I Klingler; Bruce K Tan; Julie A Poposki; Kathryn E Hulse; Whitney W Stevens; Anju T Peters; Leslie C Grammer; Kevin C Welch; Stephanie S Smith; David B Conley; Robert C Kern; Robert P Schleimer; Atsushi Kato Journal: Allergy Date: 2018-07-26 Impact factor: 13.146