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The IL-33/ST2 axis is crucial in type 2 airway responses induced by Staphylococcus 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 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 T-H(2)-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 T-H(2)-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 T-H(2) inflammation but does not prevent the allergic sensitization.
Tijdschrift: Journal of Allergy and Clinical Immunology (The)
ISSN: 0091-6749
Issue: 2
Volume: 141
Pagina's: 549 - 559
Jaar van publicatie:2018