- Title
- TNF-α and macrophages are critical for respiratory syncytial virus-induced exacerbations in a mouse model of allergic airways disease
- Creator
- Nguyen, Thi Hiep; Maltby, Steven; Simpson, Jodie L.; Eyers, Fiona; Baines, Katherine J.; Gibson, Peter G.; Foster, Paul S.; Yang, Ming
- Relation
- Journal of Immunology Vol. 196, Issue 9, p. 3547-3558
- Publisher Link
- http://dx.doi.org/10.4049/jimmunol.1502339
- Publisher
- American Association of Immunologists
- Resource Type
- journal article
- Date
- 2016
- Description
- Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-α, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVAsensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-α, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-α levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-α and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-α and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.
- Subject
- TNF-α; macrophages; respiratory syncytial virus; viral respiratory infections; asthma
- Identifier
- http://hdl.handle.net/1959.13/1323235
- Identifier
- uon:24758
- Identifier
- ISSN:0022-1767
- Language
- eng
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