Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Movement / immunology*
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Endothelial Cells / enzymology
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Endothelial Cells / immunology*
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GTP-Binding Protein alpha Subunits, Gi-Go / genetics
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GTP-Binding Protein alpha Subunits, Gi-Go / immunology
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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Glycoproteins / genetics
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Glycoproteins / immunology
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Glycoproteins / metabolism
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Intercellular Junctions / enzymology
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Intercellular Junctions / genetics
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Intercellular Junctions / immunology
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Lymph Nodes / cytology
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Lymph Nodes / enzymology
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Lymph Nodes / immunology*
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Lymphocytes / enzymology
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Lymphocytes / immunology*
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Lysophospholipids / genetics
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Lysophospholipids / immunology
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Lysophospholipids / metabolism
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Membrane Transport Proteins
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Mice
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Mice, Knockout
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Pertussis Toxin / pharmacology
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Peyer's Patches / cytology
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Peyer's Patches / immunology*
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Peyer's Patches / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / genetics
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Phosphotransferases (Alcohol Group Acceptor) / immunology*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Sphingosine / analogs & derivatives
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Sphingosine / genetics
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Sphingosine / immunology
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Sphingosine / metabolism
Substances
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Glycoproteins
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Lysophospholipids
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Membrane Transport Proteins
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Xlkd1 protein, mouse
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sphingosine 1-phosphate
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Pertussis Toxin
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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GTP-Binding Protein alpha Subunits, Gi-Go
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Sphingosine