| Summary: | Rhinovirus-induced asthma exacerbations are a major cause of morbidity and mortality in patients. Experimental clinical infection studies indicate rhinovirus augments type 2 inflammation in asthma. Additionally, asthmatic lung cells have impaired type I interferon production in response to rhinovirus stimulation. Evidence suggests co-regulation of type I interferon signalling and type 2 immunity exists; therefore, we hypothesised that type I interferon deficiency in asthma leads to the reduced regulation of type 2 immunity, resulting in exacerbation of allergen-induced type 2 inflammation during rhinovirus infection. To investigate the role of type I interferon signalling, type I interferon receptor (IFNAR1) knockout mice, an anti-IFNAR1 blocking antibody and recombinant interferon-β therapy were used in mouse models of rhinovirus-induced airways disease. Impaired IFNAR1 signalling resulted in enhanced eosinophilic inflammation in response to allergen challenge and rhinovirus infection, which was associated with increased CCL24 and Th2 chemokines CCL17 and CCL22. Recombinant interferon-β treatment had limited effects on responses to the combination of allergen and rhinovirus, but suppressed allergen-induced CCL17. In THP1-derived macrophages, interferon-β co-treatment and pre-treatment suppressed IL-4 and TNFα-induced Th2 chemokine production. Microarray analysis was performed on these cells to help identify the regulatory mechanism of type I interferon on Th2 chemokine expression. Interferon-β pre-treatment significantly upregulated PTPN6 (encoding SHP1, a phosphatase that regulates STAT6 activity) expression compared with IL-4 and TNFα-stimulated cells. Western blot analysis did not identify differences in STAT6 phosphorylation following interferon-β treatment, or differences in SHP1 protein levels. These findings support a role for type I interferon in the negative regulation of type 2 inflammation in both the presence and absence of rhinovirus; however, this mechanism has yet to be identified. Impaired interferon responses in asthma may contribute to enhanced type 2 immunity that is considered pathological in allergic airways inflammation and virus-induced asthma exacerbations.
|
|---|
