Involvement of the Lysophosphatidic Acid-Generating Enzyme Autotaxin in Lymphocyte-Endothelial Cell Interactions
Involvement of the Lysophosphatidic Acid-Generating Enzyme Autotaxin in Lymphocyte-Endothelial Cell Interactions
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DOI：
10.2353/ajpath.2008.071153
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Miyasaka, Masayuki
中科院分区：
文献类型：
--
作者：
Nakasaki, Tae;Tanaka, Toshiyuki;Miyasaka, Masayuki
自分泌运动因子（ATX）是一种具有溶血磷脂酶D活性的分泌蛋白，其从溶血磷脂酰胆碱产生溶血磷脂酸（LPA）。在这里，我们报告说，功能ATX选择性地表达在高内皮小静脉（HEV）的淋巴结和派尔集合淋巴结。ATX表达是发育调节的，与淋巴细胞向淋巴结的募集一致。在成人中，ATX表达不依赖于HEV表达的趋化因子如CCL 21和CXCL 13、先天免疫信号（包括通过TLR 4或MyD 88的信号）以及淋巴细胞跨HEV运输的程度。在慢性炎症部位的小静脉中诱导ATX表达。ATX酶产物LPA的受体在HEV内皮细胞（EC）中组成型表达。在体外，LPA诱导HEV EC的强烈形态学变化。强制ATX表达引起培养的EC响应溶血磷脂酰胆碱，上调淋巴细胞结合的EC在LPA受体依赖性的方式下，静态和流动条件。尽管体内循环ATX的消耗不影响淋巴细胞运输到淋巴结中，但基于上述数据，我们推测HEV表达的ATX原位作用于HEV以促进淋巴细胞与EC结合，并且全身循环中的ATX在该过程中不起主要作用。ATX的组织特异性失活将在其作用机制的未来研究中验证这一假设。(Am J Pathol 2008，173：1566-1576; DOI：10.2353/ajpath.2008.071153）
Autotaxin (ATX) is a secreted protein with lysophospholipase D activity that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine. Here we report that functional ATX is selectively expressed in high endothelial venules (HEVs) of both lymph nodes and Peyer's patches. ATX expression was developmentally regulated and coincided with lymphocyte recruitment to the lymph nodes. in adults, ATX expression was independent of HEV-expressed chemokines such as CCL21 and CXCL13, innate immunity signals including those via TLR4 or MyD88, and of the extent of lymphocyte trafficking across the HEVs. ATX expression was induced in venules at sites of chronic inflammation. Receptors for the ATX enzyme product LPA were constitutively expressed in HEV endothelial cells (ECs). In vitro, LPA induced strong morphological changes in HEV ECs. Forced ATX expression caused cultured ECs to respond to lysophosphatidylcholine, up-regulating lymphocyte binding to the ECs in a LPA receptor-dependent manner under both static and flow conditions. Although in vivo depletion of circulating ATX did not affect lymphocyte trafficking into the lymph nodes, we surmise, based on the above data, that ATX expressed by HEVs acts on HEVs in situ to facilitate lymphocyte binding to ECs and that ATX in the general circulation does not play a major role in this process. Tissue-specific inactivation of ATX will verify this hypothesis in future studies of its mechanism of action. (Am J Pathol 2008, 173:1566-1576; DOI: 10.2353/ajpath.2008.071153)