F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.
F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.
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DOI：
10.1038/ncomms10493
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发表时间：
2016-01-27
影响因子：
16.6
通讯作者：
van Buul JD
中科院分区：
文献类型：
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作者：
Heemskerk N;Schimmel L;Oort C;van Rijssel J;Yin T;Ma B;van Unen J;Pitter B;Huveneers S;Goedhart J;Wu Y;Montanez E;Woodfin A;van Buul JD
在免疫监视和炎症期间，白细胞通过内皮的短暂开口离开脉管系统，而不会引起血浆渗漏。然而，这一有趣现象背后的确切机制仍然未知。在这里，我们报道在白细胞浸润期间内皮屏障完整性的维持需要局部内皮RhoA循环。体外内皮RhoA缺失或体内Rho抑制可引起中性粒细胞诱导的血管渗漏，这种渗漏在中性粒细胞通过内皮层的物理运动中表现出来。局部RhoA激活启动可收缩的f -肌动蛋白结构的形成，这些结构围绕着迁移的中性粒细胞。这些围绕中性粒细胞诱导的内皮孔的结构通过基于肌动球蛋白的孔限制来防止血浆泄漏。在机制上，我们发现RhoA活性的启动涉及ICAM-1和Rho GEFs Ect2和LARG。此外，基于肌动球蛋白的内皮细胞孔限制的调控涉及ROCK2b，而不涉及ROCK1。因此，内皮细胞在内皮孔周围聚集rhoa控制的可收缩的f -肌动蛋白结构，防止白细胞外渗时血管渗漏。内皮细胞可以支持白细胞外渗而不引起血管渗漏，但这一过程的确切机制尚未完全阐明。在这里，作者表明它是通过基于肌动球蛋白的内皮孔限制来调节的，这需要局部内皮RhoA激活。
During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during the physical movement of neutrophils through the endothelial layer. Local RhoA activation initiates the formation of contractile F-actin structures that surround emigrating neutrophils. These structures that surround neutrophil-induced endothelial pores prevent plasma leakage through actomyosin-based pore confinement. Mechanistically, we found that the initiation of RhoA activity involves ICAM-1 and the Rho GEFs Ect2 and LARG. In addition, regulation of actomyosin-based endothelial pore confinement involves ROCK2b, but not ROCK1. Thus, endothelial cells assemble RhoA-controlled contractile F-actin structures around endothelial pores that prevent vascular leakage during leukocyte extravasation. Endothelial cells can support leukocyte extravasation without causing vascular leakage, but the exact mechanism underlying this process has not been fully elucidated. Here the authors show that it is regulated through actomyosin-based endothelial pore confinement, which requires local endothelial RhoA activation.