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; JST CREST, Tokyo, Japan
Naoko Sasaki
Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka, Japan
Eiji Umemoto
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka, Japan
Yutaka Uchida
Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan; JST CREST, Tokyo, Japan
Shigetomo Fukuhara
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
Yusuke Kitazawa
Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
Michiyo Okudaira
Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
Asuka Inoue
Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
Kazuo Tohya
Department of Anatomy, Kansai University of Health Sciences, Osaka, Japan
Keita Aoi
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; JST CREST, Tokyo, Japan
Junken Aoki
Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
Kenjiro Matsuno
Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan
Kiyoshi Takeda
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka, Japan
Masayuki Miyasaka
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan; MediCity Research Laboratory, University of Turku, Turku, Finland; Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Osaka, Japan
Masaru Ishii
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; JST CREST, Tokyo, Japan
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.
