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.

    • "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). "
    [Show abstract] [Hide abstract]
    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:
    No preview · Article · Jun 2015 · Toxicological Sciences
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Significant attention has been given to the role played by non-hematopoietic cells in the immune organs, including the lymph nodes, in hopes of understanding the development, maintenance, and regulation of the immune system. However, the molecular and cellular characterization of non-hematopoietic cells is still in its infancy. Here we show that non-hematopoietic cells in mouse lymph nodes can be fractionated into previously unidentified subpopulations according to the transgenic reporter expression of alpha-smooth muscle actin (αSMA). αSMA+ non-hematopoietic cells were predominantly detected in gp38+CD31- and gp38-CD31- cells. Molecular expression profiles suggest similarities between αSMA+gp38+CD31- and αSMA-gp38+CD31- subpopulations and dissimilarities between αSMA+gp38-CD31- and αSMA-gp38-CD31- subpopulations. The results indicate that αSMA is a useful marker for further understanding the molecular and cellular characteristics of non-hematopoietic cells in the lymph nodes.
    No preview · Article · May 2014 · Biochemical and Biophysical Research Communications
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lymphoid organs are meeting zones where lymphocytes come together and encounter antigens present in the blood and lymph or as delivered by cells migrating from the draining tissue bed. The exquisite efficiency of this process relies heavily on highly specialized anatomy to direct and position the various players. Gated entry and exit control access to these theaters and reticular networks and associated chemokines guide cells into the proper sections. Lymphoid tissues are remarkably plastic, being able to expand dramatically and then involute upon resolution of the danger. All of the reticular scaffolds and vascular and lymphatic components adapt accordingly. As such, the lymph node (LN) is a wonderful example of a physiologic remodeling process and is potentially a guide to study such elements in pathological settings such as fibrosis, chronic infection, and tumor metastasis. The lymphotoxin/LIGHT axis delivers critical differentiation signals that direct and hone differentiation of both reticular networks and the vasculature. Considerable progress has been made recently in understanding the mesenchymal differentiation pathways leading to these specialized networks and in the remodeling that occurs in reactive LNs. In this article, we will review some new advances in the area in terms of developmental, differentiation, and maintenance events mediated by this axis.
    Full-text · Article · Feb 2014 · Frontiers in Immunology
Show more