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IL-6 Deficiency Exacerbates Allergic Asthma and Abrogates the Protective Effect of Allergic Inflammation against Streptococcus pneumoniae Pathogenesis
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-15 , DOI: 10.4049/jimmunol.1900755
Taylor Schmit 1 , Sumit Ghosh 2 , Ram Kumar Mathur 1 , Tyler Barnhardt 1 , Ganesh Ambigapathy 1 , Min Wu 1 , Colin Combs 1 , M Nadeem Khan 3
Affiliation  

Key Points IL-6 regulates eosinophilia in a murine model of allergic asthma. Allergic inflammation confers IL-6–dependent protection against S. pneumoniae. IL-6 regulates lung barrier integrity during allergic asthma. Allergic asthma (AA) is characterized as a Th2-biased airway inflammation that can develop lung inflammation and remodeling of the respiratory tract. Streptococcus pneumoniae is a major respiratory pathogen, causing noninvasive (otitis media and pneumonia) and invasive diseases (sepsis) in humans. We sought to determine the role of IL-6 in the regulation of lung inflammation in murine AA caused by Aspergillus fumigatus as well as its consequence on the regulation of airway barrier integrity and S. pneumoniae disease. In an AA model, IL-6 deficiency led to increased lung inflammation, eosinophil recruitment, tissue pathology, and collagen deposition. Additionally, IL-6–deficient asthmatic mice exhibited reduced goblet cell hyperplasia and increased TGF-β production. These key changes in the lungs of IL-6–deficient asthmatic mice resulted in dysregulated tight junction proteins and increased lung permeability. Whereas the host response to AA protected against S. pneumoniae lung disease, the IL-6 deficiency abrogated the protective effect of allergic inflammation against S. pneumoniae pathogenesis. Consistent with in vivo data, IL-6 knockdown by small interfering RNA or the blockade of IL-6R signaling exacerbated the TGF-β–induced dysregulation of tight junction proteins, E-cadherin and N-cadherin expression, and STAT3 phosphorylation in MLE-12 epithelial cells. Our findings demonstrate a previously unrecognized role of host IL-6 response in the regulation of lung inflammation during AA and the control of S. pneumoniae bacterial disease. A better understanding of the interactions between lung inflammation and barrier framework could lead to the development of therapies to control asthma inflammation and preserve barrier integrity.

中文翻译:

IL-6缺乏会加剧过敏性哮喘并消除过敏性炎症对肺炎链球菌发病机制的保护作用

要点 IL-6 调节过敏性哮喘小鼠模型中的嗜酸性粒细胞增多。过敏性炎症赋予 IL-6 依赖性对肺炎链球菌的保护作用。IL-6 在过敏性哮喘期间调节肺屏障完整性。过敏性哮喘 (AA) 的特征是一种偏向 Th2 的气道炎症,可发展为肺部炎症和呼吸道重塑。肺炎链球菌是一种主要的呼吸道病原体,在人类中引起非侵袭性(中耳炎和肺炎)和侵袭性疾病(败血症)。我们试图确定 IL-6 在调节由烟曲霉引起的小鼠 AA 肺部炎症中的作用及其对调节气道屏障完整性和肺炎链球菌疾病的影响。在 AA 模型中,IL-6 缺乏导致肺部炎症、嗜酸性粒细胞募集、组织病理学、和胶原蛋白沉积。此外,缺乏 IL-6 的哮喘小鼠表现出杯状细胞增生减少和 TGF-β 产生增加。缺乏 IL-6 的哮喘小鼠肺部的这些关键变化导致紧密连接蛋白失调和肺通透性增加。虽然宿主对 AA 的反应可以防止肺炎链球菌肺部疾病,但 IL-6 缺乏消除了过敏性炎症对肺炎链球菌发病机制的保护作用。与体内数据一致,通过小干扰 RNA 敲低 IL-6 或阻断 IL-6R 信号传导加剧了 TGF-β 诱导的紧密连接蛋白、E-钙粘蛋白和 N-钙粘蛋白表达以及 MLE 中 STAT3 磷酸化的失调。 12个上皮细胞。我们的研究结果证明了宿主 IL-6 反应在 AA 期间调节肺部炎症和控制肺炎链球菌细菌性疾病中的先前未被认识的作用。更好地了解肺部炎症和屏障框架之间的相互作用可能会导致开发控制哮喘炎症和保持屏障完整性的疗法。
更新日期:2020-06-15
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