Wnt/β-catenin signaling reduces Bacillus Calmette-Guerin-induced macrophage necrosis through a ROS -mediated PARP/AIF-dependent pathway.
Wnt/β-catenin signaling reduces Bacillus Calmette-Guerin-induced macrophage necrosis through a ROS -mediated PARP/AIF-dependent pathway.
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Wnt/β-连环蛋白信号通过 ROS 介导的 PARP/AIF 依赖性途径减少卡介苗诱导的巨噬细胞坏死
DOI：
10.1186/s12865-015-0080-5
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发表时间：
2015-03-18
期刊：
影响因子：
3
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Wu X;Deng G;Li M;Li Y;Ma C;Wang Y;Liu X
结核分枝杆菌感染后肺泡巨噬细胞坏死已被证明在结核病的发病机制中起重要作用。我们之前的研究表明，Wnt/β-catenin信号能够通过caspase依赖途径促进分枝杆菌感染的细胞凋亡。然而，这种信号在分枝杆菌感染后巨噬细胞坏死中的功能仍然很大程度上未知。在Wnt/β-catenin信号存在的情况下，用卡介苗（Bacillus Calmette-Guerin， BCG）感染小鼠巨噬细胞RAW264.7。用细胞术和电镜观察坏死细胞的死亡情况；分别用细胞分析和酶联免疫吸附法测定活性氧（ROS）和还原性谷胱甘肽（GSH）的产生；免疫印迹法检测聚adp -核糖聚合酶1 (PARP-1)/凋亡抑制因子（AIF）信号转导活性。BCG可诱导RAW264.7巨噬细胞坏死，并伴有活性氧（ROS）的积累，呈剂量和时间依赖性。有趣的是，Wnt/β-catenin信号的增强显示了减少分枝杆菌诱导的巨噬细胞坏死的能力。机制上，Wnt/β-catenin信号的激活能够抑制bcg感染RAW264.7细胞的坏死细胞死亡，其机制是通过Wnt信号清除细胞内ROS积累并增加细胞GSH浓度。此外，免疫印迹分析进一步揭示Wnt/β-catenin信号能够部分通过PARP-1/AIF依赖性途径抑制ros介导的细胞坏死。Wnt/β-catenin信号通路的激活可以通过抑制PARP-1/AIF信号通路部分通过增加GSH的产生和清除ROS来抑制bcg诱导的巨噬细胞坏死。因此，这一发现可能为分枝杆菌感染后肺泡巨噬细胞死亡的潜在机制提供了新的见解。
Necrosis of alveolar macrophages following Mycobacterium tuberculosis infection has been demonstrated to play a vital role in the pathogenesis of tuberculosis. Our previous study demonstrated that Wnt/β-catenin signaling was able to promote mycobacteria-infected cell apoptosis by a caspase-dependent pathway. However, the functionality of this signaling in the necrosis of macrophage following mycobacterial infection remains largely unknown. Murine macrophage RAW264.7 cells were infected with Bacillus Calmette-Guerin (BCG) in the presence of Wnt/β-catenin signaling. The necrotic cell death was determined by cytometric assay and electronic microscopy; the productions of reactive oxygen species (ROS) and reduced glutathione (GSH) were measured by a cytometric analysis and an enzyme-linked immunosorbent assay, respectively; and the activity of poly (ADP-ribose) polymerase 1 (PARP-1)/apoptosis inhibition factor (AIF) signaling was examined by an immunoblotting assay. The BCG can induce RAW264.7 macrophage cells necrosis in a dose- and time-dependent manner along with an accumulation of reactive oxygen species (ROS). Intriguingly, an enhancement of Wnt/β-catenin signaling shows an ability to reduce the mycobacteria-induced macrophage necrosis. Mechanistically, the activation of Wnt/β-catenin signaling is capable of inhibiting the necrotic cell death in BCG-infected RAW264.7 cells through a mechanism by which the Wnt signaling scavenges intracellular ROS accumulation and increases cellular GSH concentration. In addition, immunoblotting analysis further reveals that Wnt/β-catenin signaling is capable of inhibiting the ROS-mediated cell necrosis in part through a PARP-1/AIF- dependent pathway. An activation of Wnt/β-catenin signaling can inhibit BCG-induced macrophage necrosis by increasing the production of GSH and scavenging ROS in part through a mechanism of repression of PARP-1/AIF signaling pathway. This finding may thus provide an insight into the underlying mechanism of alveolar macrophage cell death in response to mycobacterial infection.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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