Identification of IFN-γ and IL-27 as Critical Regulators of Respiratory Syncytial Virus–Induced Exacerbation of Allergic Airways Disease in a Mouse Model

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.

Lipopolysaccharide induces steroid‐resistant exacerbations in a mouse model of allergic airway disease collectively through IL‐13 and pulmonary macrophage activation

“…TNFα levels were unchanged in OVA‐treated mice, compared to PBS controls (Figure D). We previously demonstrated that DEX treatment has no effect on the levels of eotaxin, IL‐27p28, TNFα and IFNγ in OVA‐treated mice . Eotaxin‐1, IL‐27 (p28), TNFα, IFNγ and MCP‐1 protein levels were all increased in OVA/LPS‐treated mice compared to those in OVA‐treated mice (Figure D).…”

Regulatory cytokine function in the respiratory tract

“…IL-27 expression is increased in pulmonary macrophages following RSV exacerbation of a mouse model of peripheral sensitization and airway challenge to ovalbumin, accompanied by corticosteroidresistant lung pathology and IFN-γ-dependent AHR. 153 In this model, antibody blockade of IL-27 reduced AHR, without influencing pulmonary viral load or IFN-γ levels, 153 supporting an alternative role for IL-27 in viral exacerbation of AAD, independent of its ability to enhance IFN-γ production by CD4 + T cells. A potentially pathogenic role for IL-27 has also been suggested in chronic obstructive pulmonary disorder patients, in whom sputum IL-27 levels are elevated compared with smokers and healthy controls and inversely correlate with lung function.…”

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

“…Immediately following IAV infection, AMs contribute to the first wave of type I and type III IFNs, which are essential for the protection of the LRT from viral progression and dissemination (58,59) and the virus needs to overcome this wave of IFNs if it is to establish a successful infection (60). Additional proinflammatory cytokines produced by AMs in response to IAV including TNFα, IFNγ, IL-1α, IL-1β, and IL-18 also contribute to enhanced viral clearance through the activation of antiviral defense mechanisms in surrounding immune and epithelial cells (61)(62)(63)(64). However, a sudden and excessive production of cytokines (as are sometimes triggered by highly virulent strains of IAV), can cause alveolar hemorrhage, pulmonary edema, bronchopneumonia, and acute respiratory distress syndrome through damage to the mucosal epithelia (65)(66)(67)(68).…”