Identification of IFN-γ and IL-27 as Critical Regulators of Respiratory Syncytial Virus–Induced Exacerbation of Allergic Airways Disease in a Mouse Model
Identification of IFN-γ and IL-27 as Critical Regulators of Respiratory Syncytial Virus–Induced Exacerbation of Allergic Airways Disease in a Mouse Model
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DOI：
10.4049/jimmunol.1601950
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发表时间：
2018-01
期刊：
影响因子：
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通讯作者：
T. H. Nguyen;S. Maltby;H. Tay;F. Eyers;P. Foster;Ming Yang
中科院分区：
文献类型：
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作者：
T. H. Nguyen;S. Maltby;H. Tay;F. Eyers;P. Foster;Ming Yang
呼吸道合胞病毒（RSV）感染可诱导哮喘急性发作，导致临床症状恶化，并可能导致肺功能持续下降。急性发作是与哮喘相关的发病率和死亡率的主要原因，并显著增加了哮喘相关的医疗费用。虽然糖皮质激素用于控制急性加重，但一些患者对它们的反应很差。与类固醇耐药加重相关的潜在机制在很大程度上仍然未知。我们以前建立了一个小鼠模型的RSV诱导的过敏性气道疾病的恶化，这模拟了标志性的哮喘的临床特征。在这项研究中，我们已经确定了巨噬细胞IFN-γ和IL-27在RSV诱导的过敏性气道疾病加重的调节中的关键作用。IFN-γ和IL-27的产生是激素抵抗的，中和IFN-γ或IL-27显著抑制RSV诱导的激素抵抗的气道高反应性和气道炎症。我们以前曾暗示TNF-α和/或MCP-1激活肺巨噬细胞参与RSV诱导的急性加重机制。用TNF-α和/或MCP-1刺激肺巨噬细胞可诱导IFN-γ和IL-27的表达。我们的研究结果强调了TNF-α和MCP-1下游的IFN-γ和IL-27在RSV诱导的急性加重机制中的关键作用。因此，靶向这些因子激活的途径可能是病毒诱导的哮喘急性发作的潜在治疗方法。
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.