首页> 美国卫生研究院文献>American Journal of Translational Research >NADPH oxidase 2 inhibitor diphenyleneiodonium enhances ROS-independent bacterial phagocytosis in murine macrophages via activation of the calcium-mediated p38 MAPK signaling pathway
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NADPH oxidase 2 inhibitor diphenyleneiodonium enhances ROS-independent bacterial phagocytosis in murine macrophages via activation of the calcium-mediated p38 MAPK signaling pathway

机译:NADPH氧化酶2抑制剂联苯二碘铵通过激活钙介导的p38 MAPK信号通路来增强小鼠巨噬细胞中ROS的非细菌吞噬作用

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摘要

Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCγ, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF-α and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli-infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways.
机译:NADPH氧化酶2(NOX2)的激活触发了活性氧(ROS)的生成,这对于吞噬细胞对微生物的强大清除作用都是必不可少的。但是,尚不清楚是否抑制NOX2活化或ROS产生会影响细胞吞噬作用。在这里,我们发现经典的NOX2抑制剂联苯二碘铵(DPI)通过增强吞噬作用诱导鼠腹膜巨噬细胞摄取大肠杆菌,这种作用对温度敏感,并被细胞松弛素D以及对Syk和PLCγ的化学抑制所减弱,两个吞噬过程中参与肌动蛋白聚合的下游激酶。 DPI还降低了大肠杆菌刺激产生的TNF-α和IL-6的产生。 DPI诱导的吞噬作用增强与NOX2抑制或ROS的产生无关,但取决于细胞内钙的增加和p38 MAPK信号通路的激活。此外,DPI增强了大肠杆菌感染小鼠的细菌清除能力,减轻了炎症,从而提高了存活率。我们的结果表明,DPI通过激活钙和p38 MAPK信号通路,通过巨噬细胞促进ROS非依赖性细菌吞噬作用。

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