Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation
Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation
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DOI：
10.1074/jbc.m116.753186
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发表时间：
2017-01-06
影响因子：
4.8
通讯作者：
Wight, Thomas N.
中科院分区：
文献类型：
--
作者：
Kang, Inkyung;Harten, Ingrid A.;Wight, Thomas N.
病毒感染是导致慢性气道疾病（如哮喘）的一个恶化因素，其机制尚不清楚。聚肌苷-聚胞苷酸（poly（I：C））是一种Toll样受体3（TLR 3）激动剂，用作研究病毒感染的模拟物，已显示在动物模型中引起肺部炎症反应并加剧肺部过敏反应。以前，我们已经表明，聚（I：C）刺激肺成纤维细胞积累细胞外基质（ECM），富含透明质酸（HA）和其结合伙伴多功能蛋白聚糖，促进单核细胞粘附。在目前的研究中，我们的目的是确定多功能蛋白聚糖在体内的作用，在多聚（I：C）诱导的肺部炎症，使用他莫昔芬诱导的多功能蛋白聚糖缺陷小鼠模型（Vcan（-/-）小鼠）介导的炎症反应。在C57 B1/6小鼠中，聚（I：C）滴注显著增加了多功能蛋白聚糖和HA的积累，特别是在血管周围和支气管周围区域，这些区域富含浸润性白细胞。相比之下，多功能蛋白聚糖缺陷（Vcan（-/-））肺在这些区域中没有表现出多功能蛋白聚糖或HA的增加，支气管肺泡灌洗液中的白细胞数量显著减少，炎性趋化因子和细胞因子的表达较低。从对照小鼠分离的肺成纤维细胞的Poly（I：C）刺激在ECM中产生富含HA的电缆结构，为体外单核细胞提供基质，而来自Vcan（-/-）小鼠的肺成纤维细胞则没有。此外，在Vcan（-/-）肺成纤维细胞中，促炎细胞因子表达的增加也大大减弱。这些发现提供了强有力的证据，多功能蛋白聚糖是一个关键的炎症介质在聚（I：C）诱导的急性肺损伤，并与HA，产生ECM，促进白细胞浸润和粘附。
Viral infection is an exacerbating factor contributing to chronic airway diseases, such as asthma, via mechanisms that are still unclear. Polyinosine-polycytidylic acid (poly(I:C)), a Toll-like receptor 3 (TLR3) agonist used as a mimetic to study viral infection, has been shown to elicit inflammatory responses in lungs and to exacerbate pulmonary allergic reactions in animal models. Previously, we have shown that poly(I:C) stimulates lung fibroblasts to accumulate an extracellular matrix (ECM), enriched in hyaluronan (HA) and its binding partner versican, which promotes monocyte adhesion. In the current study, we aimed to determine the in vivo role of versican in mediating inflammatory responses in poly(I:C)-induced lung inflammation using a tamoxifen-inducible versican-deficient mouse model (Vcan(-/-) mice). In C57Bl/6 mice, poly(I:C) instillation significantly increased accumulation of versican and HA, especially in the perivascular and peribronchial regions, which were enriched in infiltrating leukocytes. In contrast, versican-deficient (Vcan(-/-)) lungs did not exhibit increases in versican or HA in these regions and had strikingly reduced numbers of leukocytes in the bronchoalveolar lavage fluid and lower expression of inflammatory chemokines and cytokines. Poly(I:C) stimulation of lung fibroblasts isolated from control mice generated HA-enriched cable structures in the ECM, providing a substrate for monocytic cells in vitro, whereas lung fibroblasts from Vcan(-/-) mice did not. Moreover, increases in proinflammatory cytokine expression were also greatly attenuated in the Vcan(-/-) lung fibroblasts. These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion.