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

doi:10.7554/eLife.41239

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

Elife. 2019 Oct 1:8:e41239. doi: 10.7554/eLife.41239.

Authors

Szandor Simmons^{1

2

3}, Naoko Sasaki⁴, Eiji Umemoto^{2

4}, Yutaka Uchida^{1

3}, Shigetomo Fukuhara⁵, Yusuke Kitazawa⁶, Michiyo Okudaira⁷, Asuka Inoue⁷, Kazuo Tohya⁸, Keita Aoi^{1

2

3}, Junken Aoki⁷, Naoki Mochizuki⁵, Kenjiro Matsuno⁶, Kiyoshi Takeda^{2

4}, Masayuki Miyasaka^{2

9

10}, Masaru Ishii^{1

2

3}

Affiliations

¹ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
² WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
³ JST CREST, Tokyo, Japan.
⁴ Department of Microbiology and Immunology, Laboratory of Immune Regulation, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁵ Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
⁶ Department of Anatomy (Macro), Dokkyo Medical University, Tochigi, Japan.
⁷ Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
⁸ Department of Anatomy, Kansai University of Health Sciences, Osaka, Japan.
⁹ MediCity Research Laboratory, University of Turku, Turku, Finland.
¹⁰ Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, Osaka, Japan.

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-G_i axis in HEVs, we generated Lyve1;Spns2^Δ/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 Cdh5^CRE-ERT2;S1pr1^Δ/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-G_i signaling, and facilitates concomitant HEV-DC interactions.

Keywords: Spinster-homologue-2; apopotosis; dendritic cells; high-endothelial venules; immunology; inflammation; lymphocyte migration; mouse; sphingosine-1-phosphate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement*
Dendritic Cells / physiology*
Endothelial Cells / physiology*
Lymph Nodes / cytology*
Lysophospholipids / metabolism*
Mice, Knockout
Sphingosine / analogs & derivatives*
Sphingosine / metabolism
Sphingosine-1-Phosphate Receptors / metabolism*

Substances

Lysophospholipids
S1pr1 protein, mouse
Sphingosine-1-Phosphate Receptors
sphingosine 1-phosphate
Sphingosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding