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高内皮细胞衍生的 S1P 调节淋巴结中树突状细胞的定位和血管完整性。

High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node.

机构信息

Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.

WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.

出版信息

Elife. 2019 Oct 1;8:e41239. doi: 10.7554/eLife.41239.

DOI:10.7554/eLife.41239
PMID:31570118
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6773441/
Abstract

While the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor-1 (S1PR1) axis is critically important for lymphocyte egress from lymphoid organs, S1PR1-activation also occurs in vascular endothelial cells (ECs), including those of the high-endothelial venules (HEVs) that mediate lymphocyte immigration into lymph nodes (LNs). To understand the functional significance of the S1P/S1PR1-G axis in HEVs, we generated conditional knockout mice for the S1P-transporter Spinster-homologue-2 (SPNS2), as HEVs express LYVE1 during development. In these mice HEVs appeared apoptotic and were severely impaired in function, morphology and size; leading to markedly hypotrophic peripheral LNs. Dendritic cells (DCs) were unable to interact with HEVs, which was also observed in ; mice and wildtype mice treated with S1PR1-antagonists. Wildtype HEVs treated with S1PR1-antagonists in vitro and -deficient HEVs show severely reduced release of the DC-chemoattractant CCL21 in vivo. Together, our results reveal that EC-derived S1P warrants HEV-integrity through autocrine control of S1PR1-G signaling, and facilitates concomitant HEV-DC interactions.

摘要

尽管鞘氨醇-1-磷酸（S1P）/鞘氨醇-1-磷酸受体-1（S1PR1）轴对于淋巴细胞从淋巴器官中迁出至关重要，但 S1PR1 的激活也发生在血管内皮细胞（ECs）中，包括高内皮静脉（HEVs），其介导淋巴细胞进入淋巴结（LNs）。为了了解 S1P/S1PR1-G 轴在 HEVs 中的功能意义，我们生成了 S1P 转运蛋白 Spinster-homologue-2（SPNS2）的条件敲除小鼠，因为 HEVs 在发育过程中表达 LYVE1。在这些小鼠中，HEVs 表现出凋亡，并且功能、形态和大小严重受损；导致周围 LNs 明显萎缩。树突状细胞（DCs）无法与 HEVs 相互作用，在；和野生型小鼠中也观察到这种情况，以及用 S1PR1 拮抗剂治疗的野生型小鼠。体外用 S1PR1 拮抗剂处理的野生型 HEVs 和 -缺陷的 HEVs 显示体内 DC 趋化因子 CCL21 的释放严重减少。总之，我们的结果表明，EC 衍生的 S1P 通过自分泌控制 S1PR1-G 信号来保证 HEV 的完整性，并促进同时发生的 HEV-DC 相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/10930507ce74/elife-41239-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/450663cb5120/elife-41239-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/7036ef1f47e2/elife-41239-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/878aed7b8643/elife-41239-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/d41a76ff2ad8/elife-41239-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/025bbef11f4e/elife-41239-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/84c79f603ef5/elife-41239-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/d2354eacc83e/elife-41239-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/10930507ce74/elife-41239-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/450663cb5120/elife-41239-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/d634efc86768/elife-41239-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/190ec905199a/elife-41239-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/3d449fea7ed3/elife-41239-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/185cd9ad0338/elife-41239-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/c0564782b1a6/elife-41239-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/7036ef1f47e2/elife-41239-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/878aed7b8643/elife-41239-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/d41a76ff2ad8/elife-41239-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/025bbef11f4e/elife-41239-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/84c79f603ef5/elife-41239-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/d2354eacc83e/elife-41239-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cacb/6773441/10930507ce74/elife-41239-fig7.jpg

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