Toussaint Marie, Jackson David J, Swieboda Dawid, Guedán Anabel, Tsourouktsoglou Theodora-Dorita, Ching Yee Man, Radermecker Coraline, Makrinioti Heidi, Aniscenko Julia, Bartlett Nathan W, Edwards Michael R, Solari Roberto, Farnir Frédéric, Papayannopoulos Venizelos, Bureau Fabrice, Marichal Thomas, Johnston Sebastian L
Airway Disease Infection Section, National Heart and Lung Institute (NHLI), Imperial College London, London, UK.
Medical Research Council (MRC) and Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
Nat Med. 2017 Jun;23(6):681-691. doi: 10.1038/nm.4332. Epub 2017 May 1.
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
呼吸道病毒感染是过敏性哮喘发作最常见的原因。2型免疫反应的放大与哮喘发作密切相关,但病毒感染如何增强2型反应尚不清楚。我们报告了人类鼻病毒感染后宿主双链DNA(dsDNA)的释放与2型过敏性炎症的加剧之间存在显著相关性。在过敏性气道超敏反应的小鼠模型中,我们发现鼻病毒感染会触发与中性粒细胞胞外陷阱(NETs)形成相关的dsDNA释放,即NETosis。我们进一步证明,通过阻断中性粒细胞弹性蛋白酶或用DNase降解NETs来抑制NETosis可保护小鼠免受2型免疫病理损伤。此外,单独注射小鼠基因组DNA足以重现鼻病毒诱导的2型免疫反应和哮喘病理的许多特征。因此,NETosis及其相关的细胞外dsDNA参与了发病机制,可能是鼻病毒诱导的哮喘发作的潜在治疗靶点。