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

Ravanetti, Lara ; Dijkhuis, Annemiek ; Dekker, Tamara ; Sabogal Pineros, Yanaika S. ; Ravi, Abilash ; Dierdorp, Barbara S. ; Erjefält, Jonas S. LU ; Mori, Michiko LU ; Pavlidis, Stelios and Adcock, Ian M. , et al. (2019) In Journal of Allergy and Clinical Immunology 143(4). p.16-1370
Abstract

Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis 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 thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral 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 exacerbations. Methods: Patients with mild asthma were experimentally infected with rhinovirus.... (More)

Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis 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 thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral 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 exacerbations. Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both. Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral 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 exacerbations.

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publication status
published
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keywords
airway hyperresponsiveness, airways epithelial cells, Asthma, dendritic cells, exacerbation, IL-33, immune response, influenza, NETosis
in
Journal of Allergy and Clinical Immunology
volume
143
issue
4
pages
16 - 1370
publisher
Elsevier
external identifiers
  • pmid:30316823
  • scopus:85056702331
ISSN
0091-6749
DOI
10.1016/j.jaci.2018.08.051
language
English
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yes
id
5de3fac3-dbe2-4a46-a01f-611bee38b996
date added to LUP
2018-11-28 14:25:02
date last changed
2020-03-29 07:31:03
@article{5de3fac3-dbe2-4a46-a01f-611bee38b996,
  abstract     = {<p>Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis 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 thymic stromal lymphopoietin (TSLP), in airway inflammation, antiviral 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 exacerbations. Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both. Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression and prevent the T<sub>H</sub>1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the T<sub>H</sub>2 response. Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.</p>},
  author       = {Ravanetti, Lara and Dijkhuis, Annemiek and Dekker, Tamara and Sabogal Pineros, Yanaika S. and Ravi, Abilash and Dierdorp, Barbara S. and Erjefält, Jonas S. and Mori, Michiko and Pavlidis, Stelios and Adcock, Ian M. and Rao, Navin L. and Lutter, René},
  issn         = {0091-6749},
  language     = {eng},
  number       = {4},
  pages        = {16--1370},
  publisher    = {Elsevier},
  series       = {Journal of Allergy and Clinical Immunology},
  title        = {IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity},
  url          = {http://dx.doi.org/10.1016/j.jaci.2018.08.051},
  doi          = {10.1016/j.jaci.2018.08.051},
  volume       = {143},
  year         = {2019},
}