Abstract
Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exacerbations are the main cause of morbidity and mortality associated with asthma, and significantly contribute to asthma-associated healthcare costs. Although glucocorticoids are used to manage exacerbations, some patients respond to them poorly. The underlying mechanisms associated with steroid-resistant exacerbations remain largely unknown. We have previously established a mouse model of RSV-induced exacerbation of allergic airways disease, which mimics hallmark clinical features of asthma. In this study, we have identified key roles for macrophage IFN-γ and IL-27 in the regulation of RSV-induced exacerbation of allergic airways disease. Production of IFN-γ and IL-27 was steroid-resistant, and neutralization of IFN-γ or IL-27 significantly suppressed RSV-induced steroid-resistant airway hyperresponsiveness and airway inflammation. We have previously implicated activation of pulmonary macrophage by TNF-α and/or MCP-1 in the mechanisms of RSV-induced exacerbation. Stimulation of pulmonary macrophages with TNF-α and/or MCP-1 induced expression of both IFN-γ and IL-27. Our findings highlight critical roles for IFN-γ and IL-27, downstream of TNF-α and MCP-1, in the mechanism of RSV-induced exacerbation. Thus, targeting the pathways that these factors activate may be a potential therapeutic approach for virus-induced asthma exacerbations.
Footnotes
This work was supported by a project grant from the National Health and Medical Research Council of Australia. S.M. is supported by the Canadian Institutes of Health Research, the University of Newcastle, and the Hunter Medical Research Institute.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AHR
- airway hyperresponsiveness
- BALF
- bronchoalveolar lavage fluid
- 2-CA
- 2-chloroadenosine
- Dex
- dexamethasone
- OVA/RSV
- RSV inoculation of OVA-sensitized/challenged mice
- PAS
- periodic acid–Schiff
- RSV
- respiratory syncytial virus.
- Received November 17, 2016.
- Accepted October 17, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.
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