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


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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    • "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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    ABSTRACT: Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system. These organs include, but are not limited to, the mucosal areas such as the lung and the gut, the liver, and the central nervous system. Homeostatic perturbation in these organs induced directly by toxicants can initiate and alter the outcome of local and systemic immunity. This review will highlight some of the identified nonimmune influences on immune homeostasis and provide summaries of how immunotoxic mechanisms of selected xenobiotics involve nonimmune cells or mediators. Thus, this review will identify data gaps and provide possible alternative mechanisms by which xenobiotics alter immune function that could be considered during immunotoxicology safety assessment. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    Toxicological Sciences 06/2015; 145(2):214-32. DOI:10.1093/toxsci/kfv060 · 3.85 Impact Factor
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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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    Frontiers in Immunology 02/2014; 5:47. DOI:10.3389/fimmu.2014.00047
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    • "Although S1P expression is dispensable for homeostatic migration of DCs (90), S1P readily augments upon inflammation and presents a leading role in guiding T lymphocytes into LVs during acute inflammation (54) but is less important for memory/effector T cell egress from tissues during chronic inflammation (42). In fact, a number of reports show how S1P directs the migration of bone marrow-derived mature DC (91), skin DCs (92), or other DC subsets (93). "
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