Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β
Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8-mediated activation of TGF-β
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DOI：
10.1172/jci45589
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Nishimura, Stephen L.
中科院分区：
文献类型：
--
作者：
Kitamura, Hideya;Cambier, Stephanie;Nishimura, Stephen L.
在慢性阻塞性肺疾病(COPD)和慢性哮喘中，气道是有害环境刺激的主要入口，这些有害环境刺激可以触发气道重塑，从而导致气道阻塞。气道重塑的重要病理成分包括纤维化和异常的先天和获得性免疫反应。成纤维细胞在间质中的定位表明，它们既参与了纤维化，也参与了免疫细胞(如树突状细胞)运输的趋化因子调节，树突状细胞是关键的抗原提呈细胞。然而，成纤维细胞的这一双重作用缺乏生理学证据。在这里，在两个生理相关的模型中--小鼠成纤维细胞中有条件地删除整合素αvβ8，以及人COPD成纤维细胞中中和整合素αvβ8，我们阐明了肺成纤维细胞分泌趋化因子引导树突状细胞运输的机制，这种机制严重依赖于成纤维细胞介导的转化生长因子-β8的激活。因此，我们的数据表明，成纤维细胞在调节肺内纤维化和免疫反应方面起着至关重要的作用。
The airway is a primary portal of entry for noxious environmental stimuli that can trigger airway remodeling, which contributes significantly to airway obstruction in chronic obstructive pulmonary disease (COPD) and chronic asthma. Important pathologic components of airway remodeling include fibrosis and abnormal innate and adaptive immune responses. The positioning of fibroblasts in interstitial spaces suggests that they could participate in both fibrosis and chemokine regulation of the trafficking of immune cells such as dendritic cells, which are crucial antigen-presenting cells. However, physiological evidence for this dual role for fibroblasts is lacking. Here, in two physiologically relevant models - conditional deletion in mouse fibroblasts of the TGF-beta-activating integrin alpha v beta 8 and neutralization of alpha v beta 8 in human COPD fibroblasts - we have elucidated a mechanism whereby lung fibroblast chemokine secretion directs dendritic cell trafficking, in a manner that is critically dependent on alpha v beta 8-mediated activation of TGF-beta by fibroblasts. Our data therefore indicate that fibroblasts have a crucial role in regulating both fibrotic and immune responses in the lung.