Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes.
Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes.
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DOI：
10.1093/intimm/dxv072
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发表时间：
2016-06
影响因子：
4.4
通讯作者：
Miyasaka M
中科院分区：
文献类型：
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作者：
Hata E;Sasaki N;Takeda A;Tohya K;Umemoto E;Akahoshi N;Ishii S;Bando K;Abe T;Kano K;Aoki J;Hayasaka H;Miyasaka M
HEV LPA 受体差异性调节淋巴细胞再循环 初始淋巴细胞通过高内皮微静脉 (HEV) 不断从血液迁移到淋巴结 (LN)。为了从 HEV 中渗出，淋巴细胞经历多个粘附步骤，包括束缚、滚动、牢固粘附和迁移。我们之前表明，自分泌运动因子（ATX）是一种产生溶血磷脂酸（LPA）的酶，在 HEV 中高表达，并且 ATX/LPA 轴在跨 HEV 的淋巴细胞迁移中发挥重要作用。然而，该轴参与淋巴细胞迁移的详细机制仍不清楚。在这里，我们发现两种 LPA 受体 LPA4 和 LPA6 在 HEV 内皮细胞 (EC) 上选择性表达，并且 LPA4 在小鼠体内跨 HEV 的淋巴细胞迁移中起主要作用。与野生型 (WT) 小鼠相比，在 LPA4 表达缺失的情况下，淋巴细胞在 HEV EC 层内大量积累。在 LPA6 表达不存在的情况下也观察到这种积累，但不太明显。使用WT淋巴细胞的过继转移实验表明，EC中的LPA4缺陷特别损害了淋巴细胞的迁移过程，而LPA6缺陷的影响并不显着。这些结果表明，HEV EC 中通过 LPA4 和 LPA6 诱发的信号差异调节外周 LN 中 HEV 的淋巴细胞外渗。
HEV LPA receptors differentially regulate lymphocyte recirculation Naive lymphocytes continuously migrate from the blood into lymph nodes (LNs) via high endothelial venules (HEVs). To extravasate from the HEVs, lymphocytes undergo multiple adhesion steps, including tethering, rolling, firm adhesion and transmigration. We previously showed that autotaxin (ATX), an enzyme that generates lysophosphatidic acid (LPA), is highly expressed in HEVs, and that the ATX/LPA axis plays an important role in the lymphocyte transmigration across HEVs. However, the detailed mechanism underlying this axis’s involvement in lymphocyte transmigration has remained ill-defined. Here, we show that two LPA receptors, LPA4 and LPA6, are selectively expressed on HEV endothelial cells (ECs) and that LPA4 plays a major role in the lymphocyte transmigration across HEVs in mice. In the absence of LPA4 expression, lymphocytes accumulated heavily within the HEV EC layer, compared to wild-type (WT) mice. This accumulation was also observed in the absence of LPA6 expression, but it was less pronounced. Adoptive transfer experiments using WT lymphocytes revealed that the LPA4 deficiency in ECs specifically compromised the lymphocyte transmigration process, whereas the effect of LPA6 deficiency was not significant. These results indicate that the signals evoked in HEV ECs via the LPA4 and LPA6 differentially regulate lymphocyte extravasation from HEVs in the peripheral LNs.