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

eLife

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[1] Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan;Department of Anatomy, Kansai University of Health Sciences, Osaka, Japan;Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan;Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan;JST CREST, Tokyo, Japan;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;Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka, Japan;Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan;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;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;

关键词: sphingosine-1-phosphate;    Spinster-homologue-2;    high-endothelial venules;    lymphocyte migration;    apopotosis;    dendritic cells;    Mouse;   

DOI  :  10.7554/eLife.41239

来源: publisher

【 摘 要 】

10.7554/eLife.41239.001While 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.

【 授权许可】

CC BY