IRF-1 Intervention in the Classical ROS-Dependent Release of NETs during LPS-Induced Acute Lung Injury in Mice
IRF-1 Intervention in the Classical ROS-Dependent Release of NETs during LPS-Induced Acute Lung Injury in Mice
复制标题
IRF-1 干预 LPS 诱导的小鼠急性肺损伤期间经典 ROS 依赖性 NET 释放
DOI：
10.1007/s10753-018-0903-7
复制
发表时间：
2019-02-01
期刊：
影响因子：
5.1
通讯作者：
Mao, Zhi
中科院分区：
文献类型：
--
作者：
Liu, Shuai;Yue, Yinyan;Mao, Zhi
之前，我们证明了中性粒细胞胞外陷阱（NETs）在脂多糖（LPS）诱导的急性肺损伤中起重要作用。然而，潜在的机制尚不清楚。在这项研究中，我们发现在小鼠中敲除干扰素调节因子1 （IRF-1）强烈减弱了支气管肺泡灌洗液中性粒细胞中NETs的产生和活性氧（ROS）的产生，并减轻了lps诱导的肺损伤和全身炎症。我们的体外实验表明，lps刺激的血小板通过两个不同的过程诱导NET释放：不依赖ros的早期/快速NETosis和后来依赖ros的经典NETosis。值得注意的是，经典的ros依赖通路在NETs的产生中起主导作用。此外，我们发现IRF-1敲除不会影响早期/快速NETosis中NETs的形成，但会显著减弱经典NETosis中ROS的产生和NETs的产生，这决定了lps刺激的血小板释放的NETs的总水平。综上所述，IRF-1缺乏在调节经典途径中ROS形成的过多NETs和保留早期/快速NETosis中产生的低net水平的保护作用中起着关键作用，这可能是急性肺损伤/急性呼吸窘迫综合征的新靶点。
Previously, we demonstrated that neutrophil extracellular traps (NETs) play an essential role in lipopolysaccharide (LPS)-induced acute lung injury. However, the underlying mechanism is unclear. In this study, we showed that knockout of interferon regulatory factor 1 (IRF-1) in mice strongly attenuated the generation of NETs and reactive oxygen species (ROS) production in neutrophils from bronchoalveolar lavage fluid and alleviated LPS-induced lung injury and systemic inflammation. Our in vitro experiments demonstrated that LPS-stimulated platelets induce NET release through two distinct processes: an ROS-independent early/rapid NETosis and a later ROS-dependent classical NETosis. Notably, the classical ROS-dependent pathway plays a dominant role in the generation of NETs. Furthermore, we showed that IRF-1 knockout does not affect the formation of NETs in early/rapid NETosis, but significantly attenuates ROS production and the generation of NETs in classical NETosis, which determines the total levels of NETs released by LPS-stimulated platelets. In conclusion, IRF-1 deficiency plays a key role in moderating the excessive NETs formed via ROS in the classical pathway and retaining the protective role of the low-NET levels generated in early/rapid NETosis, which may serve as a novel target in acute lung injury/acute respiratory distress syndrome.