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

Andrea R Teufelberger; Maria Nordengrün; Harald Braun; Tania Maes; Katrien De Grove; Gabriele Holtappels; Clara O'Brien; Sharen Provoost; Hamida Hammad; Amanda Gonçalves; Rudi Beyaert; Wim Declercq; Peter Vandenabeele; Dmitri V Krysko; Barbara M Bröker; Claus Bachert; Olga Krysko

doi:10.1016/j.jaci.2017.05.004

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

J Allergy Clin Immunol. 2018 Feb;141(2):549-559.e7. doi: 10.1016/j.jaci.2017.05.004. Epub 2017 May 19.

Authors

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

Affiliations

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.

PMID: 28532656
DOI: 10.1016/j.jaci.2017.05.004

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 T_H2-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_H2-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_H2 inflammation but does not prevent the allergic sensitization.

Keywords: Allergy; Staphylococcus aureus; asthma; sensitization; serine protease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Asthma / chemically induced
Asthma / genetics
Asthma / immunology*
Bacterial Proteins / toxicity*
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / pathology
Disease Models, Animal
Interleukin-1 Receptor-Like 1 Protein / genetics
Interleukin-1 Receptor-Like 1 Protein / immunology*
Interleukin-33 / genetics
Interleukin-33 / immunology*
Mice
Mice, Knockout
Serine Proteases / toxicity*
Signal Transduction / drug effects
Signal Transduction / genetics
Staphylococcus aureus / immunology*
Staphylococcus aureus / pathogenicity
Th2 Cells / immunology
Th2 Cells / pathology

Substances

Bacterial Proteins
Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Serine Proteases