Article

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: 12.52). 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.

    • "LECs located along the lymphatic vessels guide migrating T cells toward the lymph node (Johnson and Jackson, 2008; Podgrabinska et al., 2002). At the cortical sinuses, LECs produce sphingosine-1-phosphate, which allows for T cell egress (Pham et al., 2010). Recent evidence shows that FRCs and LECs inhibit T cell proliferation through a mechanism involving nitric oxide synthase (NOS2). "
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    • "The gp38 + CD31 À cells include fibroblastic reticular cells (FRCs), which form a three-dimensional network in the T cell zones and regulate the homeostasis and trafficking of T cells[1]. The gp38 + CD31 + and gp38 À CD31 + cells contain lymphatic endothelial cells (LECs) and blood ECs (BECs), respectively, which critically regulate the egress and entry of lymphocytes[2]. However, the molecular and cellular characterization of non-hematopoietic cells in the lymph nodes is still in its infancy. "
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    • "Recirculating lymphocytes leave the LN parenchyma by entering cortical sinuses that feed into medullary sinuses and efferent lymphatics (113). The lymphatic endothelial cells are an important source of sphingosine-1-phosphate that elicits lymphocytes to leave the parenchyma and enter the sinuses (114). Whether LTβR signaling is crucial for lymphatic function is less clear, although defects in lymphatic function were observed in LT-deficient mice (115). "
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