Migrating cells preferentially breach and integrate epithelial and endothelial monolayers at multicellular vertices. These sites are amenable to forces produced by the migrating cell and subsequent opening of the junctions. However, the cues that guide migrating cells to these entry portals, and eventually drive the transmigration process, are poorly understood. Here, we show that lymphatic endothelium multicellular junctions are the preferred sites of dendritic cell transmigration in both primary cell co-cultures and in mouse dermal explants. Dendritic cell guidance to multicellular junctions was dependent on the dendritic cell receptor CCR7, whose ligand, lymphatic endothelial chemokine CCL21, was exocytosed at multicellular junctions. Characterization of lymphatic endothelial secretory routes indicated Golgi-derived RAB6+ vesicles and RAB3+/27+ dense core secretory granules as intracellular CCL21 storage vesicles. Of these, RAB6+ vesicles trafficked CCL21 to the multicellular junctions, which were enriched with RAB6 docking factor ELKS (ERC1). Importantly, inhibition of RAB6 vesicle exocytosis attenuated dendritic cell transmigration. These data exemplify how spatially-restricted exocytosis of guidance cues helps to determine where dendritic cells transmigrate.

中文翻译：

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空间靶向趋化因子胞吐作用引导淋巴内皮多细胞连接处的轮回。


迁移细胞优先破坏并整合多细胞顶点的上皮和内皮单层。这些位点容易受到迁移细胞产生的力以及随后打开的连接的影响。然而，人们对引导细胞迁移到这些入口并最终驱动轮回过程的线索知之甚少。在这里，我们表明，在原代细胞共培养物和小鼠真皮外植体中，淋巴内皮多细胞连接处是树突状细胞迁移的首选位点。树突状细胞对多细胞连接的引导依赖于树突状细胞受体 CCR7，其配体淋巴内皮趋化因子 CCL21 在多细胞连接处被胞吐。淋巴管内皮分泌途径的表征表明高尔基体衍生的 RAB6+ 囊泡和 RAB3+/27+ 致密核心分泌颗粒作为细胞内 CCL21 储存囊泡。其中，RAB6+ 囊泡将 CCL21 运输至多细胞连接处，其中富含 RAB6 对接因子 ELKS (ERC1)。重要的是，抑制 RAB6 囊泡胞吐作用减弱了树突状细胞的迁移。这些数据例证了引导信号的空间限制性胞吐作用如何帮助确定树突状细胞迁移的位置。