Neutrophils release neutrophil extracellular traps (NETs) in response to numerous pathogenic microbes as the last suicidal resource (NETosis) in the fight against infection. Apart from the host defense function, NETs play an essential role in the pathogenesis of various autoimmune and inflammatory diseases. Therefore, understanding the molecular mechanisms of NETosis is important for regulating aberrant NET release. The initiation of NETosis after the recognition of pathogens by specific receptors is mediated by an increase in intracellular Ca2+ concentration, therefore, the use of Ca2+ ionophore A23187 can be considered a semi-physiological model of NETosis. Induction of NETosis by various stimuli depends on reactive oxygen species (ROS) produced by NADPH oxidase, however, NETosis induced by Ca2+ ionophores was suggested to be mediated by ROS produced in mitochondria (mtROS). Using the mitochondria-targeted antioxidant SkQ1 and specific inhibitors of NADPH oxidase, we showed that both sources of ROS, mitochondria and NADPH oxidase, are involved in NETosis induced by A23187 in human neutrophils. In support of the critical role of mtROS, SkQ1-sensitive NETosis was demonstrated to be induced by A23187 in neutrophils from patients with chronic granulomatous disease (CGD). We assume that Ca2+-triggered mtROS production contributes to NETosis either directly (CGD neutrophils) or by stimulating NADPH oxidase. The opening of the mitochondrial permeability transition pore (mPTP) in neutrophils treated by A23187 was revealed using the electron transmission microscopy as a swelling of the mitochondrial matrix. Using specific inhibitors, we demonstrated that the mPTP is involved in mtROS production, NETosis, and the oxidative burst induced by A23187.

中文翻译：

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线粒体通透性过渡孔参与人类嗜中性粒细胞的氧化爆发和NETosis。

中性粒细胞释放中性粒细胞胞外陷阱（NETs）作为对付感染的最后一种自杀资源（NETosis），作为对许多致病微生物的响应。除宿主防御功能外，NETs在各种自身免疫和炎性疾病的发病机理中也起着至关重要的作用。因此，了解NETosis的分子机制对于调节异常的NET释放很重要。通过特定受体识别病原体后，NETosis的启动是由细胞内Ca2 +浓度的增加介导的，因此，使用Ca2 +离子载体A23187可被视为NETosis的半生理模型。各种刺激对NETosis的诱导取决于NADPH氧化酶产生的活性氧（ROS），但是，Ca2 +离子载体引起的NETosis被认为是由线粒体中产生的ROS介导的。使用针对线粒体的抗氧化剂SkQ1和NADPH氧化酶的特异性抑制剂，我们显示ROS，线粒体和NADPH氧化酶的两种来源均与人中性粒细胞A23187诱导的NETosis有关。为了支持mtROS的关键作用，已证明A23187在患有慢性肉芽肿病（CGD）患者的嗜中性粒细胞中诱导了SkQ1敏感的NETosis。我们假设，Ca2 +触发的mtROS产生直接（或CGD中性粒细胞）或通过刺激NADPH氧化酶促成NETosis。使用电子透射显微镜观察，A23187处理的嗜中性粒细胞的线粒体通透性转换孔（mPTP）的开放是线粒体基质的溶胀。