Chronic IL-33 expression predisposes to viral-induced exacerbations of asthma by increasing type-2 inflammation and dampening antiviral immunity
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Description
Background: Rhinovirus infection triggers acute exacerbations of asthma. IL-33 is an instructive cytokine of type-2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic subjects.
Objective: To determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vivo human primary airway epithelial cells (AECs).
Methods: To model disease onset, progression, and chronicity, mice were exposed to pneumonia virus of mouse and cockroach extract in early-life and later-life, then challenged with rhinovirus. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic and healthy patients, and treated with anti-IL-33 following RV infection.
Results: Anti-IL-33 decreased type-2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high and rhinovirus challenge exacerbated the type-2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity and anti-IL-33, but not dexamethasone, promoted antiviral IFN expression and decreased viral load. RV replication was higher and IFN-lambda lower in asthmatic compared to healthy AECs. Anti-IL-33 lowered RV replication and increased IFN-λ at the gene and protein level.
Conclusion: Anti-IL-33 or dexamethasone suppressed the magnitude of type-2 inflammation during a rhinovirus-induced acute exacerbation, however only anti-IL-33 boosted antiviral immunity and lowered viral replication. The latter phenotype was replicated in RV infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defence.Key words IL-33; rhinovirus; asthma; exacerbation; antiviral
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ID Code: | 223064 | ||
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Item Type: | Contribution to Journal (Journal Article) | ||
Refereed: | Yes | ||
ORCID iD: |
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Measurements or Duration: | 13 pages | ||
Keywords: | IL-33, antiviral, asthma, exacerbation, rhinovirus | ||
DOI: | 10.1016/j.jaci.2017.07.051 | ||
ISSN: | 0091-6749 | ||
Pure ID: | 33322754 | ||
Divisions: | Past > QUT Faculties & Divisions > Faculty of Health Past > Institutes > Institute of Health and Biomedical Innovation |
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Copyright Owner: | Consult author(s) regarding copyright matters | ||
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Deposited On: | 06 Nov 2021 17:35 | ||
Last Modified: | 26 Jul 2024 12:02 |
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