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

• Published in: eLife Vol. 8
• Main Authors: Simmons, Szandor, Sasaki, Naoko, Umemoto, Eiji, Uchida, Yutaka, Fukuhara, Shigetomo, Kitazawa, Yusuke, Okudaira, Michiyo, Inoue, Asuka, Tohya, Kazuo, Aoi, Keita, Aoki, Junken, Mochizuki, Naoki, Matsuno, Kenjiro, Takeda, Kiyoshi, Miyasaka, Masayuki, Ishii, Masaru
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 01.10.2019; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; Antagonists; Antigens; apopotosis; Apoptosis; Autocrine signalling; Blood platelets; CCL21 protein; Cell activation; Cell adhesion & migration; Cell Movement; Cytology; Dendritic cells; Dendritic Cells - physiology; Emigration and immigration; Endothelial cells; Endothelial Cells - physiology; Endothelium; Enzymes; Gene expression; high-endothelial venules; Hybrid vehicles; Immunology; Immunology and Inflammation; Kinases; Laboratories; Ligands; Localization; Lymph nodes; Lymph Nodes - cytology; lymphocyte migration; Lymphocytes; Lysophospholipids - metabolism; Mice, Knockout; Morphology; Phosphates; Physiological aspects; Software; Sphingosine; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine 1-phosphate; Sphingosine-1-Phosphate Receptors - metabolism; Spinster-homologue-2; Statistical analysis; Vascular endothelial growth factor; United States; Osaka Japan; Japan; Germany; mouse; apopotosis; high-endothelial venules; Spinster-homologue-2; dendritic cells; inflammation; sphingosine-1-phosphate; immunology; lymphocyte migration
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.41239

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.