IL-33通过抑制固有和适应性抗病毒免疫介导流感病毒诱发哮喘急性发作
2019/04/10
摘要
背景：流感病毒诱发哮喘重度急性发作，但目前尚缺乏足够的治疗手段。已知IL-33水平与急性发作严重程度相关，但它在哮喘急性发作的免疫病理机制中的作用尚不明确。
目的：我们假设IL-33是哮喘急性发作的重要因素。我们干预IL-33通路，并试图分析其在气道炎症、抗病毒活性和肺功能方面的作用，以及与胸腺基质淋巴细胞生成素(TSLP)的协同作用。我们旨在揭示IL-33在气道中的主要来源和IL-33在哮喘重度急性发作中的依赖性机制。
方法：对轻度哮喘患者进行实验性鼻病毒感染。小鼠长期暴露于室内尘螨提取物中，然后感染流感病毒，以模拟人类受试者哮喘急性发作的关键特征。干预措施包括抗IL-33受体ST2抗体，抗TSLP抗体，或双抗。
结果：我们发现支气管纤毛细胞和II型肺泡细胞分别是病毒感染引起人类和小鼠哮喘急性发作过程中IL-33的主要来源。通过阻断ST2，我们证明IL-33而非TSLP是介导哮喘急性发作的必要因素。IL-33通过抑制固有和适应性抗病毒免疫，以及导致屋尘螨致敏小鼠的上皮细胞和树突状细胞抑制IFN-b的表达，抑制Th1免疫炎症中树突状细胞的形成，从而增强气道高反应性和气道炎症。IL-33也能促进气道中性粒细胞胞外诱捕网活性，抑制细胞溶解性抗病毒活性，但不影响Th2免疫反应。
结论：靶向干预IL-33/ST2轴可能证明是一种有效的病毒诱导哮喘急性发作的短期治疗方法。
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral 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.
J Allergy Clin Immunol. 2019 Apr;143(4):1355-1370.e16. doi: 10.1016/j.jaci.2018.08.051.
Abstract
Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive.
Objective: 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 thymicstromal lymphopoietin (TSLP), in airway inflammation, antiviral 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 exacerbations.
Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both.
Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-b expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response.
Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.
背景：流感病毒诱发哮喘重度急性发作，但目前尚缺乏足够的治疗手段。已知IL-33水平与急性发作严重程度相关，但它在哮喘急性发作的免疫病理机制中的作用尚不明确。
目的：我们假设IL-33是哮喘急性发作的重要因素。我们干预IL-33通路，并试图分析其在气道炎症、抗病毒活性和肺功能方面的作用，以及与胸腺基质淋巴细胞生成素(TSLP)的协同作用。我们旨在揭示IL-33在气道中的主要来源和IL-33在哮喘重度急性发作中的依赖性机制。
方法：对轻度哮喘患者进行实验性鼻病毒感染。小鼠长期暴露于室内尘螨提取物中，然后感染流感病毒，以模拟人类受试者哮喘急性发作的关键特征。干预措施包括抗IL-33受体ST2抗体，抗TSLP抗体，或双抗。
结果：我们发现支气管纤毛细胞和II型肺泡细胞分别是病毒感染引起人类和小鼠哮喘急性发作过程中IL-33的主要来源。通过阻断ST2，我们证明IL-33而非TSLP是介导哮喘急性发作的必要因素。IL-33通过抑制固有和适应性抗病毒免疫，以及导致屋尘螨致敏小鼠的上皮细胞和树突状细胞抑制IFN-b的表达，抑制Th1免疫炎症中树突状细胞的形成，从而增强气道高反应性和气道炎症。IL-33也能促进气道中性粒细胞胞外诱捕网活性，抑制细胞溶解性抗病毒活性，但不影响Th2免疫反应。
结论：靶向干预IL-33/ST2轴可能证明是一种有效的病毒诱导哮喘急性发作的短期治疗方法。
(冯敏1 张红萍1 王刚2 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（J Allergy Clin Immunol. 2019 Apr;143(4):1355-1370.e16. doi: 10.1016/j.jaci.2018.08.051.）
（J Allergy Clin Immunol. 2019 Apr;143(4):1355-1370.e16. doi: 10.1016/j.jaci.2018.08.051.）
IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral 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.
J Allergy Clin Immunol. 2019 Apr;143(4):1355-1370.e16. doi: 10.1016/j.jaci.2018.08.051.
Abstract
Background: Influenza virus triggers severe asthma exacerbations for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immunopathogenesis of exacerbations has remained elusive.
Objective: 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 thymicstromal lymphopoietin (TSLP), in airway inflammation, antiviral 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 exacerbations.
Methods: Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both.
Results: We identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 during virus driven exacerbation in human subjects and mice, respectively. By blocking ST2, we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced airway hyperresponsiveness and airway inflammation by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-b expression and prevent the TH1-promoting dendritic cell phenotype. IL-33 also boosted luminal NETosis and halted cytolytic antiviral activities but did not affect the TH2 response.
Conclusion: Interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy for virus-induced asthma exacerbations.
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