Chronic IL-33 expression predisposes to viral-induced exacerbations of asthma by increasing type-2 inflammation and dampening antiviral immunity

Publication date: Available online 22 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Rhiannon B. Werder, B Biomed Sci, Vivian Zhang, Jason P. Lynch, Natale Snape, John W. Upham, Kirsten Spann, Simon Phipps
BackgroundRhinovirus 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.ObjectiveTo 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).MethodsTo 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.ResultsAnti-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.ConclusionAnti-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.

Teaser

Using a preclinical model of chronic asthma and primary human AECs we show that anti-IL-33 boosted IFNs and lowered RV replication, suggesting that in addition to attenuating type-2 inflammation, anti-IL-33 therapy may enhance host defence.


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