Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity
Aeroallergen-induced IL-33 predisposes to respiratory virus-induced asthma by dampening antiviral immunity
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DOI：
10.1016/j.jaci.2016.02.039
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发表时间：
2016-11-01
影响因子：
14.2
通讯作者：
Phipps, Simon
中科院分区：
文献类型：
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作者：
Lynch, Jason P.;Werder, Rhiannon B.;Phipps, Simon
背景：生命早期频繁的病毒性下呼吸道感染是哮喘发病的一个独立危险因素。在后来变得致敏的儿童中，这种风险以及持续性哮喘的发展明显更大。
目的：我们试图阐明过敏原暴露和病毒感染之间协同相互作用的潜在致病过程。
方法：在小鼠生命早期和后期，用一种鼠特异性肺病毒种属（小鼠肺炎病毒[PVM]）对其进行接种，并使其暴露于低剂量蟑螂提取物（CRE），然后评估气道炎症、重塑和高反应性。用抗白细胞介素 - 33（IL - 33）或三磷酸腺苷双磷酸酶对小鼠进行治疗，以中和或阻断IL - 33的释放。
结果：单独的PVM感染或CRE暴露不会诱发疾病，而PVM/CRE共同暴露则协同诱导哮喘的标志性特征。在生命早期病毒感染期间暴露于CRE会诱导双相IL - 33反应，并损害α - 干扰素（IFN - α）和λ - 干扰素（IFN - λ）的产生，这反过来又增加了上皮病毒载量、气道平滑肌生长以及2型炎症。当CRE诱导的IL - 33释放被阻断或中和时，这些特征得到改善，而用外源性IL - 33替代CRE重现了在PVM/CRE共同暴露小鼠中观察到的表型。从机制上讲，IL - 33在体内和体外均下调蝰蛇毒素和干扰素调节因子7基因的表达，并迅速降解浆细胞样树突状细胞中白细胞介素 - 1受体相关激酶1的表达，导致Toll样受体7反应性降低和IFN - α产生受损。
结论：我们确定了IL - 33一种迄今尚未被认识的功能，即作为一种强大的天然抗病毒免疫抑制剂，并证明IL - 33在哮喘发病和进展过程中对呼吸道病毒和过敏原暴露之间的协同相互作用有重要贡献。
Background: Frequent viral lower respiratory infections in early life are an independent risk factor for asthma onset. This risk and the development of persistent asthma are significantly greater in children who later become sensitized.Objective: We sought to elucidate the pathogenic processes that underlie the synergistic interplay between allergen exposures and viral infections.Methods: Mice were inoculated with a murine-specific Pneumovirus species (pneumonia virus of mice [PVM]) and exposed to low-dose cockroach extract (CRE) in early and later life, and airway inflammation, remodeling, and hyperreactivity assessed. Mice were treated with anti-IL-33 or apyrase to neutralize or block IL-33 release.Results: PVM infection or CRE exposure alone did not induce disease, whereas PVM/CRE coexposure acted synergistically to induce the hallmark features of asthma. CRE exposure during viral infection in early life induced a biphasic IL-33 response and impaired IFN-alpha and IFN-lambda production, which in turn increased epithelial viral burden, airway smooth muscle growth, and type 2 inflammation. These features were ameliorated when CRE-induced IL-33 release was blocked or neutralized, whereas substitution of CRE with exogenous IL-33 recapitulated the phenotype observed in PVM/CRE-coexposed mice.Mechanistically, IL-33 downregulated viperin and interferon regulatory factor 7 gene expression and rapidly degraded IL-1 receptor-associated kinase 1 expression in plasmacytoid dendritic cells both in vivo and in vitro, leading to Toll-like receptor 7 hyporesponsiveness and impaired IFN-alpha production.Conclusion: We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.