High-endothelial cell-derived s1p regulates dendritic cell localization and vascular integrity in the lymph node

Szandor Simmons, Naoko Sasaki, Eiji Umemoto, Yutaka Uchida, Shigetomo Fukuhara, Yusuke Kitazawa, Michiyo Okudaira, Asuka Inoue, Kazuo Tohya, Keita Aoi, Junken Aoki, Naoki Mochizuki, Kenjiro Matsuno, Kiyoshi Takeda, Masayuki Miyasaka, Masaru Ishii

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


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.

Original languageEnglish
Article numbere41239
Publication statusPublished - 2019 Oct


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