@article{7e3e4db0ee334325a3b5fdfe9ef6209d,
title = "High-endothelial cell-derived s1p regulates dendritic cell localization and vascular integrity in the lymph node",
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-Gi axis in HEVs, we generated Lyve1;Spns2Δ/Δ 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 Cdh5CRE-ERT2;S1pr1Δ/Δ mice and wildtype mice treated with S1PR1-antagonists. Wildtype HEVs treated with S1PR1-antagonists in vitro and Lyve1-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-Gi signaling, and facilitates concomitant HEV-DC interactions.",
author = "Szandor Simmons and Naoko Sasaki and Eiji Umemoto and Yutaka Uchida and Shigetomo Fukuhara and Yusuke Kitazawa and Michiyo Okudaira and Asuka Inoue and Kazuo Tohya and Keita Aoi and Junken Aoki and Naoki Mochizuki and Kenjiro Matsuno and Kiyoshi Takeda and Masayuki Miyasaka and Masaru Ishii",
note = "Funding Information: We thank Dr. Junichi Kikuta, Norie Yoshizumi, Mai Shirazaki, Masami Kasaoka, Yumiko Mayjima, Dr. Hiroaki Hemmi, Furi Fukuda, Dr. Tetsuya Honda, and Dr. Tomoko Hirano for technical assistance. We thank Dr. Kuniyuki Kano for providing charcoal-stripped FCS. We thank Dr. Yoshiaki Kubota for kindly providing Cdh5CRE-ERT2 mice, and we are grateful to Dr. Richard L Proia and Dr. Sylvio Gut-kind for kindly giving us S1pr1f/f mice. Furthermore, we thank Dr. Ronald Germain, Dr. Takaharu. Okada, Dr. Alison Hobro, Dr. Sidonia Fagarasan, Dr. Fritz Melchers, Dr. Tsuneyasu Kaisho, and Dr. Kenji Kabashima for active discussions, technical advice and critical suggestions for the manuscript. This work was supported by Grants-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS; JP25253070 and JP16H02619 to MI); Grants-in-Aid for Young Scientists (B) from the JSPS (JP26860329 to SS); grants from the Takeda Science Foundation (to MI); from the Uehara Memorial Foundation (to MI); from the Kanae Foundation for the Promotion of Medical Sciences (to MI); and from the Kishimoto Foundation (to SS). Funding Information: We thank Dr. Junichi Kikuta, Norie Yoshizumi, Mai Shirazaki, Masami Kasaoka, Yumiko Mayjima, Dr. Hiroaki Hemmi, Furi Fukuda, Dr. Tetsuya Honda, and Dr. Tomoko Hirano for technical assistance. We thank Dr. Kuniyuki Kano for providing charcoal-stripped FCS. We thank Dr. Yoshiaki Kubota for kindly providing Cdh5CRE-ERT2 mice, and we are grateful to Dr. Richard L Proia and Dr. Sylvio Gut-kind for kindly giving us S1pr1f/f mice. Furthermore, we thank Dr. Ronald Germain, Dr. Takaharu Okada, Dr. Alison Hobro, Dr. Sidonia Fagarasan, Dr. Fritz Melchers, Dr. Tsuneyasu Kaisho, and Dr. Kenji Kabashima for active discussions, technical advice and critical suggestions for the manuscript. This work was supported by Grants-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS; JP25253070 and JP16H02619 to MI); Grants-in-Aid for Young Scientists (B) from the JSPS (JP26860329 to SS); grants from the Takeda Science Foundation (to MI); from the Uehara Memorial Foundation (to MI); from the Kanae Foundation for the Promotion of Medical Sciences (to MI); and from the Kishimoto Foundation (to SS). Publisher Copyright: {\textcopyright} Simmons et al.",
year = "2019",
month = oct,
doi = "10.7554/eLife.41239",
language = "English",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}
