Tripathi Jitendra Kumar, Sharma Atul, Sukumaran Pramod, Sun Yuyang, Mishra Bibhuti Bhusan, Singh Brij Bhan, Sharma Jyotika
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
FASEB J. 2018 Jun 15;32(12):fj201800605. doi: 10.1096/fj.201800605.
Neutrophil extracellular trap (NET) formation constitutes an important extracellular antimicrobial function of neutrophils that plays a protective role in bacterial pneumonia. Formation of reactive oxygen species (ROS) such as highly diffusible hydrogen peroxide (HO) is a hallmark of oxidative stress during inflammatory lung conditions including pneumonia. However, the impact of exogenous ROS on NET formation and the signaling pathway involved in the process is not completely understood. Here we demonstrate that the ROS-sensing, nonselective, calcium-permeable channel transient receptor potential melastatin 2 (TRPM2) is required for NET formation in response to exogenous HO. This TRPM2-dependent HO-mediated NET formation involved components of autophagy and activation of AMPK and p38 MAPK, but not PI3K and AKT. Primary neutrophils from Trpm2 mice fail to activate this pathway with a block in NET release and a concomitant decrease in their antimicrobial capacity. Consequently, Trpm2 mice were highly susceptible to pneumonic infection with Klebsiella pneumoniae owing to an impaired NET formation and high bacterial burden despite increased neutrophil infiltration in their lungs. These results identify a key role of TRPM2 in regulating NET formation by exogenous ROS via AMPK/p38 activation and autophagy machinery, as well as a protective antimicrobial role of TRPM2 in pneumonic bacterial infection.-Tripathi, J. K., Sharma, A., Sukumaran, P., Sun, Y., Mishra, B. B., Singh, B. B., Sharma, J. Oxidant sensor cation channel TRPM2 regulates neutrophil extracellular trap formation and protects against pneumoseptic bacterial infection.
中性粒细胞胞外陷阱（NET）形成是中性粒细胞重要的胞外抗菌功能，在细菌性肺炎中发挥保护作用。活性氧（ROS）如具有高扩散性的过氧化氢（HO）的形成是包括肺炎在内的炎症性肺部疾病中氧化应激的标志。然而，外源性ROS对NET形成的影响以及该过程中涉及的信号通路尚未完全明确。在此，我们证明，ROS感应、非选择性、钙通透性通道瞬时受体电位香草酸亚型2（TRPM2）是外源性HO诱导NET形成所必需的。这种依赖TRPM2的HO介导的NET形成涉及自噬成分以及AMPK和p38 MAPK的激活，但不涉及PI3K和AKT。来自Trpm2基因敲除小鼠的原代中性粒细胞无法激活该信号通路，导致NET释放受阻，同时抗菌能力下降。因此，尽管Trpm2基因敲除小鼠肺部中性粒细胞浸润增加，但由于NET形成受损和细菌载量高，它们对肺炎克雷伯菌肺炎高度易感。这些结果表明，TRPM2在外源性ROS通过激活AMPK/p38和自噬机制调节NET形成过程中起关键作用，以及TRPM2在肺部细菌感染中具有保护性抗菌作用。-特里帕蒂，J.K.，夏尔马，A.，苏库马兰，P.，孙，Y.，米什拉，B.B.，辛格，B.B.，夏尔马，J.氧化还原传感器阳离子通道TRPM2调节中性粒细胞胞外陷阱形成并预防肺部细菌感染
