Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy
Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy
复制标题
DOI：
10.1152/ajpcell.00108.2013
复制
发表时间：
2013-08-01
影响因子：
5.5
通讯作者：
McCarty, Owen J. T.
中科院分区：
文献类型：
--
作者：
Itakura, Asako;McCarty, Owen J. T.
自噬是细胞稳态和存活的重要细胞机制，通过自噬，受损的细胞蛋白被隔离在自噬体囊泡中并通过溶酶体机制清除。自噬途径还通过由免疫细胞（包括巨噬细胞和嗜中性粒细胞）介导的病原体清除机制在免疫和炎症中起重要作用。特别是，最近的研究表明，自噬活性是释放中性粒细胞胞外陷阱（NET）所必需的，代表了一种独特的主动中性粒细胞死亡形式，即NETosis。虽然NET的形成是有益的宿主防御入侵病原体，在病理条件下，促进过度NETosis的机制仍然不清楚。在本研究中，我们的目的是表征哺乳动物雷帕霉素靶蛋白（mTOR）在NETosis中的作用。由于mTOR激酶被认为是许多哺乳动物细胞（包括中性粒细胞）中自噬的关键调节因子，因此我们假设mTOR可能通过调节自噬活性在NET释放中发挥调节作用。我们的数据表明，mTOR通路的药理学抑制加速了用细菌衍生肽甲酰-Met-Leu-Phe（fMLP）刺激中性粒细胞后NET释放的速率，而mTOR抑制剂增强了自噬体形成。这种增加的mTOR依赖性NET释放对呼吸爆发的抑制或细胞骨架动力学的阻断敏感。总体而言，本研究证明了mTOR通路在协调导致NETosis的中性粒细胞活化下游的细胞内信号传导事件中的关键作用。
Autophagy is an essential cellular mechanism for cell homeostasis and survival by which damaged cellular proteins are sequestered in autophagosomal vesicles and cleared through lysosomal machinery. The autophagy pathway also plays an important role in immunity and inflammation via pathogen clearance mechanisms mediated by immune cells, including macrophages and neutrophils. In particular, recent studies have revealed that autophagic activity is required for the release of neutrophil extracellular traps (NETs), representing a distinct form of active neutrophil death, namely NETosis. Although NET formation is beneficial during host defense against invading pathogens, the mechanisms that promote excessive NETosis under pathological conditions remain ill defined. In the present study, we aimed to characterize the role of the mammalian target of rapamycin (mTOR) in NETosis. As mTOR kinase is known as a key regulator of autophagy in many mammalian cells including neutrophils, we hypothesized that mTOR may play a regulatory role in NET release by regulating autophagic activity. Our data show that the pharmacological inhibition of the mTOR pathway accelerated the rate of NET release following neutrophil stimulation with the bacteria-derived peptide formyl-Met-Leu-Phe (fMLP), while autophagosome formation was enhanced by mTOR inhibitors. This increased mTOR-dependent NET release was sensitive to inhibition of respiratory burst or blockade of cytoskeletal dynamics. Overall, this study demonstrates a pivotal role for the mTOR pathway in coordinating intracellular signaling events downstream of neutrophil activation leading to NETosis.