Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning.
Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Galphai-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell-cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
Pham
Trung H M
TH
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Baluk
Peter
P
Xu
Ying
Y
Grigorova
Irina
I
Bankovich
Alex J
AJ
Pappu
Rajita
R
Coughlin
Shaun R
SR
McDonald
Donald M
DM
Schwab
Susan R
SR
Cyster
Jason G
JG
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007365:Intercellular Junctions / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology*; D008246:Lysophospholipids / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D037342:Pertussis Toxin / Q000494:pharmacology; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099157:Sphingosine Kinase
D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D006023:Glycoproteins; D008246:Lysophospholipids; D026901:Membrane Transport Proteins; D037342:Pertussis Toxin; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C492273:LYVE1 protein, mouse; C060506:sphingosine 1-phosphate