细胞外组蛋白通过内皮细胞中的 TLR4 触发氧化应激依赖性 NF-kB/CAM 通路诱导,Journal of Physiology and Biochemistry

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细胞外组蛋白通过内皮细胞中的 TLR4 触发氧化应激依赖性 NF-kB/CAM 通路诱导
Journal of Physiology and Biochemistry ( IF 3.7 ) Pub Date : 2022-12-05 , DOI: 10.1007/s13105-022-00935-z
Daniel Pérez-Cremades _{1,

2} , Carlos Bueno-Betí _{1,

2} , José Luis García-Giménez _{1,

2,

3} , José Santiago Ibañez-Cabellos _{1,

2,

3} , Federico V Pallardó _{1,

2,

3} , Carlos Hermenegildo _{1,

2} , Susana Novella _{1,

2}

Affiliation

据报道，细胞外组蛋白通过增加血管通透性、凝血病和炎症来加剧不同的病理生理过程。在本研究中，我们利用人脐静脉内皮细胞 (HUVEC) 阐明了细胞外组蛋白 (10–100 µg/mL) 浓度如何依赖性地增加细胞质活性氧 (ROS) 的产生。此外，我们确定环氧合酶 (COX) 和 NADPH 氧化酶 (NOX) 活性是细胞外组蛋白处理的 HUVEC 中 ROS 产生的来源。这种 COX/NOX 介导的 ROS 产生还参与组蛋白处理的 HUVEC 中 NF-kB 活性和细胞粘附分子（VCAM1 和 ICAM1）表达的增强。最后，通过使用不同的Toll样受体（TLR）拮抗剂，我们证明了 TLR4 在内皮细胞中胞外组蛋白触发的 CAM 过度表达中的作用。总之，我们的数据表明，通过 TLR4 信号传导，细胞外组蛋白增加内皮细胞活化，这是一种涉及增加 COX 和 NOX 介导的 ROS 的机制。这些发现增加了我们对细胞外组蛋白如何增强组蛋白释放作为病理过程一部分的疾病中的全身炎症反应的理解。

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Extracellular histones trigger oxidative stress-dependent induction of the NF-kB/CAM pathway via TLR4 in endothelial cells

Extracellular histones have been reported to aggravate different pathophysiological processes by increasing vascular permeability, coagulopathy, and inflammation. In the present study, we elucidate how extracellular histones (10–100 µg/mL) concentration dependently increase cytosolic reactive oxygen species (ROS) production using human umbilical vein endothelial cells (HUVECs). Furthermore, we identify cyclooxygenase (COX) and NADPH oxidase (NOX) activity as sources of ROS production in extracellular histone-treated HUVEC. This COX/NOX-mediated ROS production is also involved in enhanced NF-kB activity and cell adhesion molecules (VCAM1 and ICAM1) expression in histone-treated HUVEC. Finally, by using different toll-like receptor (TLR) antagonists, we demonstrate the role of TLR4 in CAMs overexpression triggered by extracellular histones in endothelial cells. In conclusion, our data suggest that through TLR4 signaling, extracellular histones increase endothelial cell activation, a mechanism involving increased COX- and NOX-mediated ROS. These findings increase our understanding on how extracellular histones enhance systemic inflammatory responses in diseases in which histone release occurs as part of the pathological processes.

更新日期：2022-12-07

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