Journal Article

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

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

2019

Overview

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.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 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