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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.

Pubmed ID: 20026661

Authors

  • Pham TH
  • Baluk P
  • Xu Y
  • Grigorova I
  • Bankovich AJ
  • Pappu R
  • Coughlin SR
  • McDonald DM
  • Schwab SR
  • Cyster JG

Journal

The Journal of experimental medicine

Publication Data

January 18, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL024136
  • Agency: NHLBI NIH HHS, Id: R01 HL059157
  • Agency: NHLBI NIH HHS, Id: R01 HL065590
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cell Movement
  • Endothelial Cells
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Glycoproteins
  • Intercellular Junctions
  • Lymph Nodes
  • Lymphocytes
  • Lysophospholipids
  • Mice
  • Mice, Knockout
  • Pertussis Toxin
  • Peyer's Patches
  • Phosphotransferases (Alcohol Group Acceptor)
  • Signal Transduction
  • Sphingosine