Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
FASEB J. 2019 Feb;33(2):2599-2609. doi: 10.1096/fj.201801329R. Epub 2018 Oct 3.
Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.
中性粒细胞的募集和血浆渗出是对损伤或感染的免疫反应的关键因素。活化的中性粒细胞刺激内皮屏障的开放；然而，其潜在机制在很大程度上仍不清楚。在这项研究中，我们确定了炎症性激肽释放酶-激肽系统的关键作用以及随后形成的缓激肽在中性粒细胞诱导的血管渗漏中的作用。在急性炎症的小鼠和仓鼠模型中，缓激肽生成和信号转导的抑制剂显著减少了趋化因子激活中性粒细胞时的血浆渗出。缺乏缓激肽 B 受体或因子 XII（激肽释放酶-激肽系统的启动子）的小鼠，中性粒细胞驱动的渗漏也受到抑制。在人内皮细胞单层中，从活化的中性粒细胞分泌的物质诱导细胞骨架重排，导致以缓激肽依赖的方式形成细胞旁间隙。作为一种机制基础，我们发现中性粒细胞衍生的肝素结合蛋白 (HBP/azurocidin) 将缓激肽前体高分子量激肽原从内皮细胞中置换出来，从而使激肽原被中性粒细胞和血浆蛋白酶切割成缓激肽。这些数据为中性粒细胞打开内皮屏障的信号通路提供了新的见解，并将激肽释放酶-激肽系统确定为急性炎症反应中治疗干预的靶点。-肯内，E.，拉斯穆森，J.，伦内，T.，维埃拉，M. L.，米勒-埃斯特尔，W.，赫瓦尔德，H.，林德博姆，L. 中性粒细胞利用激肽释放酶-激肽系统在急性炎症中打开内皮屏障。
