Local microvascular leakage promotes trafficking of activated neutrophils to remote organs.
Local microvascular leakage promotes trafficking of activated neutrophils to remote organs.
复制标题
局部微血管渗漏促进活化的中性粒细胞向远端器官的运输。
DOI：
10.1172/jci133661
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Owen-Woods C
中科院分区：
文献类型：
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作者：
Owen-Woods C
血浆蛋白的微血管通透性增加和中性粒细胞迁移是先天免疫的标志，也是许多炎症性疾病的关键特征。尽管中性粒细胞可以促进微血管渗漏，但血管通透性对中性粒细胞运输的影响尚不清楚。在这里，通过应用共聚焦活体显微镜，我们报告血管通透性增强刺激引起中性粒细胞反向跨内皮细胞迁移（rTEM）的显着频率。此外，具有选择性微血管通透性增强缺陷的小鼠（VEC-Y685F-ki）显示中性粒细胞 rTEM 的发生率降低。从机制上讲，血管渗漏增加促进间质趋化因子进入血流，这种反应支持腔内到腔内的中性粒细胞 TEM。通过开发体内细胞标记方法，我们为 rTEM 中性粒细胞的全身传播提供了直接证据，并表明它们表现出激活的表型，并且能够运输到肺部，在那里它们的存在与血管损伤区域一致。总的来说，我们证明微血管渗漏的增加逆转了小静脉壁上定向信号的定位，从而导致参与渗出的中性粒细胞重新进入体循环。这一级联事件提供了一种机制来解释局部组织炎症和血管通透性如何诱发远端器官（尤其是肺部）的下游病理效应。
Increased microvascular permeability to plasma proteins and neutrophil emigration are hallmarks of innate immunity and key features of numerous inflammatory disorders. Although neutrophils can promote microvascular leakage, the impact of vascular permeability on neutrophil trafficking is unknown. Here, through the application of confocal intravital microscopy, we report that vascular permeability–enhancing stimuli caused a significant frequency of neutrophil reverse transendothelial cell migration (rTEM). Furthermore, mice with a selective defect in microvascular permeability enhancement (VEC-Y685F-ki) showed reduced incidence of neutrophil rTEM. Mechanistically, elevated vascular leakage promoted movement of interstitial chemokines into the bloodstream, a response that supported abluminal-to-luminal neutrophil TEM. Through development of an in vivo cell labeling method we provide direct evidence for the systemic dissemination of rTEM neutrophils, and showed them to exhibit an activated phenotype and be capable of trafficking to the lungs where their presence was aligned with regions of vascular injury. Collectively, we demonstrate that increased microvascular leakage reverses the localization of directional cues across venular walls, thus causing neutrophils engaged in diapedesis to reenter the systemic circulation. This cascade of events offers a mechanism to explain how local tissue inflammation and vascular permeability can induce downstream pathological effects in remote organs, most notably in the lungs.