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

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‐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. Within these LN, dendritic cells (DCs) were unable to interact with HEVs, which was also observed in VEcad‐CREERT2‐S1PR1Δ/Δ mice and wildtype mice treated with S1PR1‐antagonists. Wildtype HEVs treated with S1PR1‐antagonists in vitro, as well as Spns2‐deficient HEVs in vivo, show severely reduced release of the DC‐chemoattractant CCL21. Together, our results reveal that EC‐derived S1P warrants HEV‐integrity through autocrine control of S1PR1‐Gi signaling, and facilitates concomitant HEV‐DC interactions.Support or Funding InformationThis work was supported by Grants‐in‐Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS; JP25253070 and JP16H02619 to M.I.); Grants‐in‐Aid for Young Scientists (B) from the JSPS (JP26860329 to S.S.); grants from the Takeda Science Foundation (to M.I.); from the Uehara Memorial Foundation (to M.I.); from the Kanae Foundation for the Promotion of Medical Sciences (to M.I.); and from the Kishimoto Foundation (to S.S.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.