The IL-33/ST2 axis is crucial in type 2 airway responses induced by Staphylococcus aureus–derived serine protease–like protein D

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 2; pp. 549 - 559.e7
• Main Authors: Teufelberger, Andrea R., Nordengrün, Maria, Braun, Harald, Maes, Tania, De Grove, Katrien, Holtappels, Gabriele, O'Brien, Clara, Provoost, Sharen, Hammad, Hamida, Gonçalves, Amanda, Beyaert, Rudi, Declercq, Wim, Vandenabeele, Peter, Krysko, Dmitri V., Bröker, Barbara M., Bachert, Claus, Krysko, Olga
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2018; Elsevier Limited
• Subjects: Allergens; Allergies; Allergy; Allergy and Immunology; Animal models; Asthma; CD4 antigen; Cytokines; Dendritic cells; Enzyme-linked immunosorbent assay; Eosinophilia; Eotaxin; Flow cytometry; Hyperplasia; Hyperreactivity; Immune system; Immunoglobulin E; Immunohistochemistry; Inflammation; Inflammatory diseases; Interleukin 13; Interleukin 5; Leukocytes (eosinophilic); Lymph nodes; Lymphocytes T; Lymphoid cells; Polyps; Protein D; Proteins; RAG gene; Recombination; Respiratory tract diseases; Rodents; sensitization; serine protease; Software; Staphylococcus aureus; Toll-like receptors; United Kingdom > UK; Belgium; PAR; Allergy; PAS; HRP; AECII; FACS; Spl; GFP; HDM; ILC2; DMEM; NF-κB; FITC; TUNEL; sensitization; TLR; Rag2; Staphylococcus aureus; MLKL; ProSPC; TSLP; BALF; asthma; sST2; serine protease; APC; PE; OVA; PerCP; pMLKL; DC; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Prosurfactant protein C; Mixed lineage kinase domain–like protein; Peridinin-chlorophyll-protein complex; Staphylococcus aureus–derived serine protease–like protein; Periodic acid–Schiff; Recombination-activating gene; Soluble ST2 receptor; Toll-like receptor; Nuclear factor κB; Airway epithelial cell type II; Bronchoalveolar lavage fluid; Protease-activated receptor; Fluorescein isothiocyanate; Horseradish peroxidase; Dulbecco modified Eagle medium; Allophycocyanin; Ovalbumin; Dendritic cells; House dust mite; Fluorescence-activated cell sorting; Thymic stromal lymphopoietin; phosphorylated mixed lineage kinase domain–like protein; Green fluorescent protein; Type 2 innate lymphoid cell; Phycoerythrin
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.05.004

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. We investigated the role of recombinant SplD in driving TH2-biased responses and IgE formation in a murine model of allergic asthma. 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. 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. 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. [Display omitted]