Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Nat Commun. 2016 Dec 16;7:13696. doi: 10.1038/ncomms13696.
Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support T2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.
哮喘具有多种特征，包括气道高反应性、炎症和重塑。TNF 超家族成员 TNFSF14（LIGHT）通过与受体 TNFRSF14（HVEM）相互作用，可支持 T2 细胞的产生和存活，并促进哮喘小鼠模型中的气道重塑，但 TNFSF14 在这种情况下发挥作用的机制尚不完全清楚。在这里，我们发现鼠和人肥大细胞（MC）表达 TNFRSF14，并且 TNFSF14：TNFRSF14 相互作用可以增强 IgE 介导的 MC 信号转导和介质产生。在哮喘的小鼠模型中，用抗原致敏后给予中和抗体或基因敲除 Tnfrsf14 阻断 TNFRSF14，可降低抗原特异性 IgG 和 IgE 抗体、气道高反应性、气道炎症和气道重塑的血浆水平。最后，通过分析在移植表达或不表达 TNFRSF14 的 MC 后两种类型的基因敲除 MC 小鼠，我们表明 MC 上的 TNFRSF14 表达显著促进了哮喘病理的多种特征的发展。
Zotero 插件
