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Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 12/2009; 207(1):17-27. DOI: 10.1084/jem.20091619
Source: PubMed

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.

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    • "Furthermore, animals that conditionally lack Sphk1/Sphk2 in Lyve1 ? lymphatic endothelium (Pham et al. 2010) show a comparable reduction of lymphocytes in the LNs of Spns2-deficient mice. This Spns2-unique power of controlling the recirculation of almost all lymphocyte populations in traffic between different tissues will be the basis of further intense studies, and elucidate whether or not S1P is the only factor that is secreted via Spns2 and solely controls the recirculation of interstitial lymphocytes in both lymph and blood, respectively. "
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    Archivum Immunologiae et Therapiae Experimentalis 11/2013; 62(2). DOI:10.1007/s00005-013-0264-8 · 2.82 Impact Factor
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    • "S1P lyase (Schwab et al., 2005), genetic knockout of sphingosine kinases (Pham et al., 2010), S1P transporter (Spns2; Fukuhara et al., 2012), or the lipid phos­ phate phosphatase­3 (LPP3; Bréart et al., 2011) results in the attenuation of lym­ phocyte egress, and lymphopenia. Sim­ ilar mechanisms may also be operative in the trafficking of dendritic cells, NKT cells, and hematopoietic progenitor cells (Massberg et al., 2007; Cyster and Schwab, 2012). "
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    • "Previously published study has indicated that sphingosine-1-phosphate receptor-1 (S1P 1 ), the predominant sphingosine-1-phosphate (S1P) receptor expressed on lymphocytes, is important for cellular localization in these cortical sinuses and is required for lymphocyte egress from secondary lymphoid organs. Lymphocyte response to S1P via S1P 1 overcomes the action of retention signals (such as lymphoid chemokines ) or other molecules and promotes egress (Cyster, 2005; Massberg and Von Andrian, 2006; Pappu et al., 2007; Schwab and Cyster, 2007; Pham, 2008; Grigorova et al., 2009; Pham et al., 2010). How S1P 1 signaling in lymphocytes promotes egress remains unknown. "
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