A1 Refereed original research article in a scientific journal
High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node
Authors: Simmons S, Sasaki N, Umemoto E, Uchida Y, Fukuhara S, Kitazawa Y, Okudaira M, Inoue A, Tohya K, Aoi K, Aoki J, Mochizuki N, Matsuno K, Takeda K, Miyasaka M, Ishii M
Publisher: eLife Sciences Publications Ltd
Publication year: 2019
Journal: eLife
Journal name in source: eLife
Volume: 8
Number of pages: 32
ISSN: 2050-084X
eISSN: 2050-084X
DOI: https://doi.org/10.7554/eLife.41239
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/45539508
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.
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