| First Author | Simmons S | Year | 2019 |
| Journal | Elife | Volume | 8 |
| PubMed ID | 31570118 | Mgi Jnum | J:283692 |
| Mgi Id | MGI:6376816 | Doi | 10.7554/eLife.41239 |
| Citation | Simmons S, et al. (2019) High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node. Elife 8:e41239 |
| abstractText | 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;Spns2(Delta/Delta) 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(Delta/Delta) 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. |
