Molecular Cell Biology Laboratory, Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center Amsterdam, University of Amsterdam, 1066 CX Amsterdam, the Netherlands.
Department of Physiology, Free University Medical Center, 1081 HV Amsterdam, the Netherlands.
J Immunol. 2018 Mar 1;200(5):1790-1801. doi: 10.4049/jimmunol.1700702. Epub 2018 Jan 31.
Leukocyte transendothelial migration is key to inflammation. Leukocytes first start rolling over the inflamed endothelium, followed by firmly adhering to it. Under inflammatory conditions, endothelial cells express small finger-like protrusions that stick out into the lumen. The function and regulation of these structures are unclear. We present evidence that these ICAM-1- and F-actin-rich endothelial finger-like protrusions are filopodia and function as adhesive structures for leukocytes to transit from rolling to crawling but are dispensable for diapedesis. Mechanistically, these structures require the motor function of myosin-X, activity of the small GTPase Cdc42, and p21-activated kinase 4. Moreover, myosin-X expression is under control of TNF-α-mediated c-Jun N-terminal kinase activity and is upregulated in human atherosclerotic regions. To our knowledge, this is the first study to identify that regulation of endothelial filopodia is crucial for leukocyte extravasation, in particular for the initiation of leukocyte adhesion under flow conditions.
白细胞穿越血管内皮细胞迁移是炎症反应的关键。白细胞首先开始在发炎的血管内皮上滚动，然后牢固地附着在上面。在炎症条件下，内皮细胞表达出小手指状的突起，这些突起伸出到管腔中。这些结构的功能和调节尚不清楚。我们提供的证据表明，这些富含 ICAM-1 和 F-肌动蛋白的内皮状指状突起是丝状伪足，作为白细胞从滚动到爬行的黏附结构，但对于穿越血管壁没有必要。从机制上讲，这些结构需要肌球蛋白-X 的运动功能、小 GTPase Cdc42 的活性和 p21 激活激酶 4。此外，肌球蛋白-X 的表达受 TNF-α 介导的 c-Jun N 端激酶活性的控制，并在上皮样动脉粥样硬化区域上调。据我们所知，这是首次研究确定内皮丝状伪足的调节对于白细胞渗出是至关重要的，特别是对于在流动条件下白细胞黏附的起始是至关重要的。
