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

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Background: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.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: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.Graphical abstract

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