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. 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.
Highlights
Lymph nodes (LNs) are essential sites for maturation, activation, homeostatic expansion, and tolerance induction of lymphocytes (Girard et al, 2012; von Andrian and Mempel, 2003), and serve as an immunological interface between the blood and lymph circulatory systems
In the present study we have demonstrated that chemotactic recruitment of lymph-derived Dendritic cells (DCs) to high-endothelial venules (HEVs) is controlled by a SPNS2-dependent S1P release from HEVs, and autocrine S1PR1-Gi signalling on high-endothelial cells, which collectively warrants survival of HEVs
We followed the development of hypotrophic peripheral LNs (pLNs), which occurs as a consequence of severely impaired HEV-morphology and function in Lyve1;Spns2D/D mice
Summary
Lymph nodes (LNs) are essential sites for maturation, activation, homeostatic expansion, and tolerance induction of lymphocytes (Girard et al, 2012; von Andrian and Mempel, 2003), and serve as an immunological interface between the blood and lymph circulatory systems. Depletion of DCs in vivo led to the downregulation of PNAd and HEV-specific genes (Moussion and Girard, 2011) that is Glycam-1, FucT-VII and Chst, the latter two encoding for the HEV-unique enzymes fucosyltransferase-7 and N-acetylglucosamine 6-O-sulphotransferase 2 (GlcNAc6ST-2), respectively (Rosen, 2004) These drastic phenotypical changes of HEVs resulted in impaired lymphocyte immigration to LNs and were explained by interrupted stimulation of lymphotoxin-b receptor (LTbr) signalling that is evoked by LTa1b2, provided by DCs (Moussion and Girard, 2011; Browning et al, 2005). S1PR1-Gi-signalling regulates high-endothelial cell survival, HEV-integrity and coincidentally CCL21 production and release from high-endothelial cells This negatively influences HEV-DC interactions necessary for normal morphology and function of HEVs, which allows controlled lymphocyte immigration into pLNs
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