Abstract
SummaryRespiratory syncytial virus (RSV) infection often exacerbates bronchial asthma, but there is no licensed RSV vaccine or specific treatments. Here we show that RSV-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration. When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups. These exacerbations in the HDM/RSV group were attenuated in MMP-12-deficient mice and mice treated with MMP408, a selective MMP-12 inhibitor, but not in mice treated with dexamethasone. Finally, M2-like macrophages produced MMP-12, and its production was promoted by increase of IFN-β-induced IL-4 receptor expression with RSV infection. Thus, targeting MMP-12 represents a potentially novel therapeutic strategy for the exacerbation of asthma.
Highlights
Asthma is a chronic airway inflammatory disease characterized by wheezing and increasing airway hyperresponsiveness (AHR) with allergic airway inflammation that promotes persistent physiological and structural remodeling events in the lungs (Galli et al, 2008)
We show that Respiratory syncytial virus (RSV)-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration
When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/ RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups
Summary
Asthma is a chronic airway inflammatory disease characterized by wheezing and increasing airway hyperresponsiveness (AHR) with allergic airway inflammation that promotes persistent physiological and structural remodeling events in the lungs (Galli et al, 2008). Several environmental allergens and/or viruses are known to trigger and exacerbate asthma via their effects on innate and adaptive immune cells (Jackson et al, 2011; O’Byrne, 2011). Asthma has traditionally been viewed as a Th2 disease with increased IgE levels, eosinophilic inflammation, and M2 macrophages contributing to AHR (Robinson et al, 1992), whereas the findings in an asthma mouse model suggested that Th1 cells and neutrophils modulate the disease (Cui et al, 2005). Recent attention has been directed at characterizing factors that modulate immune cell responses in response to environmental allergens
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