IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity

Publication date: Available online 12 October 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Lara Ravanetti, Annemiek Dijkhuis, Tamara Dekker, Yanaika S. Sabogal Pineros, Abilash Ravi, Barbara S. Dierdorp, Jonas S. Erjefält, Michiko Mori, Stelios Pavlidis, Ian M. Adcock, Navin L. Rao, René Lutter

Abstract

Background

Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive.

Objective

We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with TSLP, in airway inflammation, anti-viral activity and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbation.

Methods

Mild asthmatic patients were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite (HDM) extract and then infected with influenza to resemble key features of exacerbations in humans. Interventions included anti–IL-33-receptor ST2 and/or anti–TSLP.

Results

We identified bronchial ciliated cells and Type-II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in humans and mice, respectively. By blocking ST2 we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced AHR and airway inflammation by suppressing innate and adaptive anti-viral responses and by instructing epithelial cells and dendritic cells (DCs) of HDM-sensitized mice to dampen IFN-β expression and prevent the Th1-promoting DCs phenotype. IL-33 also boosted luminal NETosis and halted cytolytic anti-viral activities, but did not affect the Th2-response.

Conclusion

Interventions targeting the IL-33/ST2 axis could prove an effective acute, short-term therapy for virus-induced asthma exacerbation.

Graphical abstract

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