Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA.
1] Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA [2] Department of Biomedical Engineering, Northwestern University, Chicago, Illinois 60611, USA.
Nat Commun. 2015 Mar 12;6:6574. doi: 10.1038/ncomms7574.
Activation of the NLRP3 inflammasome and subsequent maturation of IL-1β have been implicated in acute lung injury (ALI), resulting in inflammation and fibrosis. We investigated the role of vimentin, a type III intermediate filament, in this process using three well-characterized murine models of ALI known to require NLRP3 inflammasome activation. We demonstrate that central pathophysiologic events in ALI (inflammation, IL-1β levels, endothelial and alveolar epithelial barrier permeability, remodelling and fibrosis) are attenuated in the lungs of Vim(-/-) mice challenged with LPS, bleomycin and asbestos. Bone marrow chimeric mice lacking vimentin have reduced IL-1β levels and attenuated lung injury and fibrosis following bleomycin exposure. Furthermore, decreased active caspase-1 and IL-1β levels are observed in vitro in Vim(-/-) and vimentin-knockdown macrophages. Importantly, we show direct protein-protein interaction between NLRP3 and vimentin. This study provides insights into lung inflammation and fibrosis and suggests that vimentin may be a key regulator of the NLRP3 inflammasome.
NLRP3 炎性小体的激活以及随后的 IL-1β 成熟已被牵连到急性肺损伤（ALI）中，导致炎症和纤维化。我们使用三种众所周知需要 NLRP3 炎性小体激活的 ALI 小鼠模型，研究了细胞角蛋白，一种 III 型中间丝在这个过程中的作用。我们证明，在 LPS、博来霉素和石棉刺激的 Vim(-/-) 小鼠的肺部，ALI 的中心病理生理事件（炎症、IL-1β 水平、内皮和肺泡上皮屏障通透性、重塑和纤维化）减弱。骨髓嵌合小鼠缺乏细胞角蛋白，在博来霉素暴露后，IL-1β 水平降低，肺损伤和纤维化减轻。此外，在体外观察到 Vim(-/-) 和细胞角蛋白敲低的巨噬细胞中活性 caspase-1 和 IL-1β 水平降低。重要的是，我们显示 NLRP3 和细胞角蛋白之间存在直接的蛋白-蛋白相互作用。这项研究提供了对肺部炎症和纤维化的深入了解，并表明细胞角蛋白可能是 NLRP3 炎性小体的关键调节因子。
