Song Jian, Zhang Xueli, Buscher Konrad, Wang Ying, Wang Huiyu, Di Russo Jacopo, Li Lixia, Lütke-Enking Stefan, Zarbock Alexander, Stadtmann Anika, Striewski Paul, Wirth Benedikt, Kuzmanov Ivan, Wiendl Heinz, Schulte Dörte, Vestweber Dietmar, Sorokin Lydia
Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, 48149 Muenster, Germany; Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany.
Cells-in-Motion Cluster of Excellence, University of Muenster, 48149 Muenster, Germany; Department of Anesthesiology and Intensive Care Medicine, University of Muenster, 48149 Muenster, Germany.
Cell Rep. 2017 Jan 31;18(5):1256-1269. doi: 10.1016/j.celrep.2016.12.092.
Endothelial basement membranes constitute barriers to extravasating leukocytes during inflammation, a process where laminin isoforms define sites of leukocyte exit; however, how this occurs is poorly understood. In addition to a direct effect on leukocyte transmigration, we show that laminin 511 affects endothelial barrier function by stabilizing VE-cadherin at junctions and downregulating expression of CD99L2, correlating with reduced neutrophil extravasation. Binding of endothelial cells to laminin 511, but not laminin 411 or non-endothelial laminin 111, enhanced transendothelial cell electrical resistance (TEER) and inhibited neutrophil transmigration. Data suggest that endothelial adhesion to laminin 511 via β1 and β3 integrins mediates RhoA-induced VE-cadherin localization to cell-cell borders, and while CD99L2 downregulation requires integrin β1, it is RhoA-independent. Our data demonstrate that molecular information provided by basement membrane laminin 511 affects leukocyte extravasation both directly and indirectly by modulating endothelial barrier properties.
内皮基底膜在炎症过程中构成白细胞外渗的屏障，在此过程中，层粘连蛋白异构体决定白细胞渗出的部位；然而，其具体发生机制尚不清楚。除了对白细胞迁移有直接影响外，我们还发现层粘连蛋白511通过稳定连接处的血管内皮钙黏蛋白（VE-cadherin）并下调CD99L2的表达来影响内皮屏障功能，这与中性粒细胞外渗减少相关。内皮细胞与层粘连蛋白511结合，而非层粘连蛋白411或非内皮层粘连蛋白111结合，可增强跨内皮细胞电阻（TEER）并抑制中性粒细胞迁移。数据表明，内皮细胞通过β1和β3整合素与层粘连蛋白511的黏附介导RhoA诱导的VE-钙黏蛋白定位于细胞间边界，虽然CD99L2的下调需要整合素β1，但它不依赖于RhoA。我们的数据表明，基底膜层粘连蛋白511提供的分子信息通过调节内皮屏障特性直接和间接影响白细胞外渗。
