Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning
Open accessAbstract
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 Gαi-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.
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LECs and BECs synthesize S1P, which binds S1PR1 on DCs and T cells to promote their mobilization toward initial LVs.
“LECs and BECs also synthesize S1P, which binds the S1P receptor type 1 (S1PR1) on DCs ( Figure 3a ) and T cells to promote their mobilization toward initial LVs (106, 107).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [107]
The Concluding remarks (page not supplied) identify LECs as the main source of S1P needed for lymphocyte egress from lymph nodes; the introductory passage links lymphocyte S1P1 to migration into lymph-node cortical sinuses. The paper reports BEC production of S1P only in vitro. Its Results and discussion (page not supplied) find no apparent difference in DC trafficking in Sphk-deficient mice, so it does not establish S1P–S1PR1-driven DC mobilization toward initial lymphatic vessels; nor does it place the demonstrated T-cell migration at those vessels. (LLM, conf=0.88)
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- Authors
- Pham, T. H. M., Baluk, P., Xu, Y., Grigorova, I., Bankovich, A. J., Pappu, R., Coughlin, S. R., McDonald, D. M., Schwab, S. R., & Cyster, J. G.
- Affiliations
- Howard Hughes Medical Institute (US)
- Howard Hughes Medical Institute and Department of Microbiology and Immunology 1 , 2 , and 3
- New York University (US)
- Corresponding author
- Cyster, Jason G.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2009-12-21
- Volume
- 207
- Issue
- 1
- Pages
- 17-27
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2812554
- OpenAlex
- W2156445027
- Cited by
- 444
- References
- 0
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 19 · 2023: 23 · 2022: 32 · 2021: 37 · 2020: 31 · 2019: 35 · 2018: 34 · 2017: 22 · 2016: 39 · 2015: 22 · 2014: 34 · 2013: 21 · 2012: 29
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (R01HL059157, P01HL024136, R01HL065590)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Keywords
- sphingosine kinase, sphingosine-1-phosphate, lymphocyte egress, lymphatic endothelial cells, lymph nodes, Peyer's patches, LYVE-1, sphingosine kinase 1, sphingosine kinase 2, Gαi, pertussis toxin, VE-cadherin, lymphatic development
- MeSH terms
- Sphingosine Kinase, Animals, Cell Movement, Glycoproteins, Intercellular Junctions, Lymph Nodes, Lymphocytes, Lysophospholipids, Peyer's Patches, Sphingosine, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, GTP-Binding Protein alpha Subunits, Gi-Go, Membrane Transport Proteins, Pertussis Toxin, Endothelial Cells, Mice
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