Abstract
SUMMARYDevelopment of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma.
Highlights
Asthma in childhood is strongly linked to atopy and a Th2-biased immunological response to chronic allergen exposure (Sly et al, 2008; Holt and Sly, 2012)
Progression to persistent asthma is likely to be related to relatively stable changes in the immunological response and/or to structural changes in the airway wall referred to as airway remodelling, which might in turn be a consequence of epigenetic changes, possibly driven by environmental factors (Kumar et al, 2009; Martino and Prescott, 2011)
We have recently described a model of the interaction between early-life respiratory viral infection and allergen exposure in the development of an asthmatic phenotype in mice (Siegle et al, 2010)
Summary
Asthma in childhood is strongly linked to atopy and a Th2-biased immunological response to chronic allergen exposure (Sly et al, 2008; Holt and Sly, 2012). Birth cohort studies suggest that there is a greatly increased risk of development of clinical features of asthma in children who suffer wheezing lower respiratory tract infections in early life, notably with rhinovirus and respiratory syncytial virus (RSV), on a background of sensitisation to aeroallergens (Kusel et al, 2007; Jackson et al, 2012; Kusel et al, 2012). Progression to persistent asthma is likely to be related to relatively stable changes in the immunological response and/or to structural changes in the airway wall referred to as airway remodelling, which might in turn be a consequence of epigenetic changes, possibly driven by environmental factors (Kumar et al, 2009; Martino and Prescott, 2011). It is difficult to investigate such changes and to assess the altered immunological response in the airway wall in children with asthma
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