Constitutive Lymphocyte Transmigration across the Basal Lamina of High Endothelial Venules Is Regulated by the Autotaxin/Lysophosphatidic Acid Axis
Constitutive Lymphocyte Transmigration across the Basal Lamina of High Endothelial Venules Is Regulated by the Autotaxin/Lysophosphatidic Acid Axis
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DOI：
10.4049/jimmunol.1202025
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Miyasaka, Masayuki
中科院分区：
文献类型：
--
作者：
Bai, Zhongbin;Cai, Linjun;Miyasaka, Masayuki
淋巴结高内皮微静脉（HEVs）的淋巴细胞外渗对于维持免疫稳态至关重要，但其分子机制仍不清楚。在这篇文章中，我们报告说，淋巴细胞穿越基底层的HEVs的调节，至少部分，自分泌运动因子（ATX）和它的最终产品，溶血磷脂酸（LPA）。ATX是一种HEV相关胞外酶，其从体循环中丰富的溶血磷脂酰胆碱（LPC）产生LPA。与ATX在HEVs中的选择性表达一致，LPA在HEVs上被组成性地和特异性地检测到。在体内，抑制ATX损害淋巴细胞从HEV外渗，诱导淋巴细胞在内皮细胞（EC）和亚EC隔室内的积累;这种损害被LPA消除。在体外，LPA和LPC诱导的HEV EC的运动显着增加; LPC的效果被废除ATX抑制，而LPA的效果被废除ATX/LPA受体抑制。在体外迁移试验中，ATX抑制损害了在HEV EC下方迁移的淋巴细胞的释放，并且这些缺陷被LPA消除。LPA的这种作用依赖于HEV EC中肌球蛋白II的活性。总的来说，这些结果强烈表明，HEV相关的ATX产生LPA本地，LPA，反过来，作用于HEV EC，以增加其运动性，促进动态淋巴细胞-HEV相互作用和随后的淋巴细胞在稳态下穿过基底层的HEV。免疫学杂志，2013，190：2036-2048。
Lymphocyte extravasation from the high endothelial venules (HEVs) of lymph nodes is crucial for the maintenance of immune homeostasis, but its molecular mechanism remains largely unknown. In this article, we report that lymphocyte transmigration across the basal lamina of the HEVs is regulated, at least in part, by autotaxin (ATX) and its end-product, lysophosphatidic acid (LPA). ATX is an HEV-associated ectoenzyme that produces LPA from lysophosphatidylcholine (LPC), which is abundant in the systemic circulation. In agreement with selective expression of ATX in HEVs, LPA was constitutively and specifically detected on HEVs. In vivo, inhibition of ATX impaired the lymphocyte extravasation from HEVs, inducing lymphocyte accumulation within the endothelial cells (ECs) and sub-EC compartment; this impairment was abrogated by LPA. In vitro, both LPA and LPC induced a marked increase in the motility of HEV ECs; LPC's effect was abrogated by ATX inhibition, whereas LPA's effect was abrogated by ATX/LPA receptor inhibition. In an in vitro transmigration assay, ATX inhibition impaired the release of lymphocytes that had migrated underneath HEV ECs, and these defects were abrogated by LPA. This effect of LPA was dependent on myosin II activity in the HEV ECs. Collectively, these results strongly suggest that HEV-associated ATX generates LPA locally; LPA, in turn, acts on HEV ECs to increase their motility, promoting dynamic lymphocyte-HEV interactions and subsequent lymphocyte transmigration across the basal lamina of HEVs at steady state. The Journal of Immunology, 2013, 190: 2036-2048.