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Chronic airway inflammatory diseases, such as chronic rhinosinusitis with nasal polyps and asthma, show increased nasalStaphylococcus aureuscolonization.Staphylococcus aureus–derived serine protease–like protein (Spl) D and other closely related proteases secreted byS aureushave 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.TheS aureus–derived protein SplD is a potent allergen ofS aureusand 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.