IL-33通过阻止先天性和适应性抗病毒免疫来驱动流感诱发的哮喘急性发作
2018/10/24
摘要
背景：流感病毒引发严重的哮喘急性发作，但没有足够的治疗方法。已知IL-33水平与恶化严重程度相关，但其在急性发作的免疫发病机制中的作用仍然难以捉摸。我们假设IL-33是驱动哮喘急性发作所必需的。我们介入了IL-33级联反应，并试图在与TSLP的协同作用中剖析其在气道炎症，抗病毒活性和肺功能方面的作用。我们的目的是揭示气道中IL-33的主要来源和IL-33依赖性机制，这些机制是严重哮喘急性发作的基础。
方法：轻度哮喘患者实验性感染鼻病毒。将小鼠长期暴露于屋尘螨（HDM）提取物中，然后用流感感染，以类似于人类恶化的关键特征。干预包括抗IL-33受体ST2和/或抗TSLP。
结果：我们分别在人和小鼠的病毒驱动的恶化过程中将支气管纤毛细胞和II型肺泡细胞鉴定为IL-33的主要局部来源。通过阻断ST2，我们证明了IL-33而不是TSLP是驱动急性加重所必需的。IL-33通过抑制先天性和适应性抗病毒反应以及通过指导HDM致敏小鼠的上皮细胞和树突细胞（DC）来抑制IFN-β表达并阻止Th1促进的树突细胞表型来增强气道高反应性和气道炎症。IL-33还增强了腔内静脉炎并停止了细胞溶解性抗病毒活性，但并未影响Th2反应。
结论：针对IL-33/ST2轴的干预措施可以证明是一种有效的急性短期治疗，可用于病毒引起的哮喘急性发作。
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity.
Ravanetti L, Dijkhuis A, Dekker T, Sabogal Pineros YS, Ravi A, Dierdorp BS, Erjefält JS, Mori M, Pavlidis S, Adcock IM, Rao NL, Lutter R.
Abstract
BACKGROUND:Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with TSLP, in airway inflammation, anti-viral activity and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbation.
METHODS:Mild asthmatic patients were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite (HDM) extract and then infected with influenza to resemble key features of exacerbations in humans. Interventions included anti-IL-33-receptor ST2 and/or anti-TSLP.
RESULTS:We identified bronchial ciliated cells and Type-II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in humans and mice, respectively. By blocking ST2 we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced AHR and airway inflammation by suppressing innate and adaptive anti-viral responses and by instructing epithelial cells and dendritic cells (DCs) of HDM-sensitized mice to dampen IFN-β expression and prevent the Th1-promoting DCs phenotype. IL-33 also boosted luminal NETosis and halted cytolytic anti-viral activities, but did not affect the Th2-response.
CONCLUSIONS:Interventions targeting the IL-33/ST2 axis could prove an effective acute, short-term therapy for virus-induced asthma exacerbation.
背景：流感病毒引发严重的哮喘急性发作，但没有足够的治疗方法。已知IL-33水平与恶化严重程度相关，但其在急性发作的免疫发病机制中的作用仍然难以捉摸。我们假设IL-33是驱动哮喘急性发作所必需的。我们介入了IL-33级联反应，并试图在与TSLP的协同作用中剖析其在气道炎症，抗病毒活性和肺功能方面的作用。我们的目的是揭示气道中IL-33的主要来源和IL-33依赖性机制，这些机制是严重哮喘急性发作的基础。
方法：轻度哮喘患者实验性感染鼻病毒。将小鼠长期暴露于屋尘螨（HDM）提取物中，然后用流感感染，以类似于人类恶化的关键特征。干预包括抗IL-33受体ST2和/或抗TSLP。
结果：我们分别在人和小鼠的病毒驱动的恶化过程中将支气管纤毛细胞和II型肺泡细胞鉴定为IL-33的主要局部来源。通过阻断ST2，我们证明了IL-33而不是TSLP是驱动急性加重所必需的。IL-33通过抑制先天性和适应性抗病毒反应以及通过指导HDM致敏小鼠的上皮细胞和树突细胞（DC）来抑制IFN-β表达并阻止Th1促进的树突细胞表型来增强气道高反应性和气道炎症。IL-33还增强了腔内静脉炎并停止了细胞溶解性抗病毒活性，但并未影响Th2反应。
结论：针对IL-33/ST2轴的干预措施可以证明是一种有效的急性短期治疗，可用于病毒引起的哮喘急性发作。
(中日友好医院呼吸与危重症医学科 王瑞茵 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2018 Oct 11. pii: S0091-6749(18)31434-9. doi: 10.1016/j.jaci.2018.08.051. [Epub ahead of print].)
(J Allergy Clin Immunol. 2018 Oct 11. pii: S0091-6749(18)31434-9. doi: 10.1016/j.jaci.2018.08.051. [Epub ahead of print].)
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity.
Ravanetti L, Dijkhuis A, Dekker T, Sabogal Pineros YS, Ravi A, Dierdorp BS, Erjefält JS, Mori M, Pavlidis S, Adcock IM, Rao NL, Lutter R.
Abstract
BACKGROUND:Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with TSLP, in airway inflammation, anti-viral activity and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbation.
METHODS:Mild asthmatic patients were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite (HDM) extract and then infected with influenza to resemble key features of exacerbations in humans. Interventions included anti-IL-33-receptor ST2 and/or anti-TSLP.
RESULTS:We identified bronchial ciliated cells and Type-II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in humans and mice, respectively. By blocking ST2 we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced AHR and airway inflammation by suppressing innate and adaptive anti-viral responses and by instructing epithelial cells and dendritic cells (DCs) of HDM-sensitized mice to dampen IFN-β expression and prevent the Th1-promoting DCs phenotype. IL-33 also boosted luminal NETosis and halted cytolytic anti-viral activities, but did not affect the Th2-response.
CONCLUSIONS:Interventions targeting the IL-33/ST2 axis could prove an effective acute, short-term therapy for virus-induced asthma exacerbation.
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气道上皮细胞衍生的集落刺激因子-1促进过敏原致敏
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年轻人与老年人不同上呼吸道微生物菌群及其哮喘相关功能基因
