Smalley, D. M. & Ley, K. L-selectin: mechanisms and physiological significance of ectodomain cleavage. J. Cell. Mol. Med. 9, 255-266

Cardiovascular Research Center and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, 22908-1294, USA.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 04/2005; 9(2):255-66. DOI: 10.1111/j.1582-4934.2005.tb00354.x
Source: PubMed

ABSTRACT L-selectin is a cell adhesion molecule consisting of a large, highly glycosylated, extracellular domain, a single spanning transmembrane domain and a small cytoplasmic tail. It is expressed on most leukocytes and is involved in their rolling on inflamed vascular endothelium prior to firm adhesion and transmigration. It is also required for the constitutive trafficking of lymphocytes through secondary lymphoid organs. Like most adhesion molecules, L-selectin function is regulated by a variety of mechanisms including gene transcription, post-translational modifications, association with the actin cytoskeleton, and topographic distribution. In addition, it is rapidly downregulated by proteolytic cleavage near the cell surface by ADAM-17 (TACE) and at least one other "sheddase". This process of "ectodomain shedding" results in the release of most of the extracellular portion of L-selectin from the cell surface while retaining the cytoplasmic, transmembrane, and eleven amino acids of the extracellular domain on the cell. This review will examine the mechanism(s) of L-selectin ectodomain shedding and discuss the physiological implications.

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Available from: Klaus Ley, Sep 26, 2015
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    • "L-selectin (CD62L) is a cell adhesion molecule expressed on the surface of most circulating leukocytes, including T cells. It is also present as a functionally active soluble form in the blood (Raffler et al., 2005), which significantly increases during acute or chronic inflammation (Smalley and Ley, 2005). In this study, our aim was to evaluate whether the soluble form of L-selectin is associated with anti-JCV antibody indices in natalizumab-treated RRMS patients, which would suggest the potential of sL-selectin in the assessment of PML risk. "
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    ABSTRACT: In relapsing-remitting MS (RRMS) patients treated with natalizumab, the low level of L-selectin-expressing CD4+ T cells has been associated with the risk of progressive multifocal leukoencephalopathy (PML). In this study, our aim was to correlate the levels of soluble L-selectin and the anti-JCV antibody index in the sera of RRMS patients treated with natalizumab. This study included 99 subjects, including 44 RRMS patients treated with natalizumab, 30 with interferon beta (IFN-β) and 25 healthy controls. The levels of soluble l-selectin (sL-selectin) in sera were measured by ELISA, and the anti-JC Virus (JCV) antibody index was determined by the second-generation ELISA (STRATIFY JCV(TM) DxSelect(TM)) assay. A significant correlation was found between the levels of sL-selectin and anti-JCV antibody indices in sera in the natalizumab-treated patients (r=0.402; p=0.007; n=44), but not in those treated with IFN-β. This correlation became even stronger in JCV seropositive patients treated with natalizumab for longer than 18 months (r=0.529; p=0.043; n=15). The results support the hypothesis of sL-selectin being connected to the anti-JCV antibody index values and possibly cellular L-selectin. Measurement of serum sL-selectin should be evaluated further as a potential biomarker for predicting the risk of developing PML. Copyright © 2015 Elsevier B.V. All rights reserved.
    07/2015; 4(4). DOI:10.1016/j.msard.2015.06.008
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    • "Following cellular activation, leukocytes increase expression of L-selectin, which is then shed by proteolytic cleavage into a soluble form that inhibits leukocyte adhesion, and hence modulates the speed of leukocyte rolling (Hafezi-Moghadam et al., 2001; Smalley and Ley, 2005). Selectins bind to specific ligands through weak interactions, which enable leukocytes to roll on endothelium; among them, the P-selectin glycoprotein ligand-1 (PSGL-1), constitutively expressed by leukocytes, binds all three members of the selectin family (Moore, 1998). "
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    ABSTRACT: Accumulated evidence points to a key role for endocannabinoids in cell migration, and here we sought to characterize the role of these substances in early events that modulate communication between endothelial cells and leukocytes. We found that 2-arachidonoylglycerol (2-AG) was able to initiate and complete the leukocyte adhesion cascade, by modulating the expression of selectins. A short exposure of primary human umbilical vein endothelial cells (HUVECs) to 2-AG was sufficient to prime them towards an activated state: within 1hour of treatment, endothelial cells showed time-dependent plasma membrane expression of P- and E-selectins, which both trigger the initial steps (i.e., capture and rolling) of leukocyte adhesion. The effect of 2-AG was mediated by CB1 and CB2 receptors and was long lasting, because endothelial cells incubated with 2-AG for 1hour released the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) for up to 24hours. Consistently, TNF-α-containing medium was able to promote leukocyte recruitment: human Jurkat T cells grown in conditioned medium derived from 2-AG-treated HUVECs showed enhanced L-selectin and P-selectin glycoprotein ligand-1 (PSGL1) expression, as well as increased efficiency of adhesion and trans-migration. In conclusion, our in vitro data indicate that 2-AG, by acting on endothelial cells, might indirectly promote leukocyte recruitment, thus representing a potential therapeutic target for treatment of diseases where impaired endothelium/leukocyte interactions take place.
    The international journal of biochemistry & cell biology 04/2014; 51(1). DOI:10.1016/j.biocel.2014.03.028 · 4.05 Impact Factor
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    • "A decrease in L-selectin expression in cattle is observed in a bovine leukocyte adhesion deficiency, which demonstrates a reduction in neutrophil migration [17] and reduces the recruitment of neutrophils into tissues [15]. L-selectin shedding occurs via enzymatic cleavage "sheddases" at membrane-proximal sites and is involved in the migration of neutrophils induced by chemokines and with transendothelial processes [23]. Moreover, it is possible that the inhibition of neutrophil ROS production during acute ruminal acidosis is involved in the reduction of PAF-induced L-selectin shedding observed in our experimental procedure. "
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    ABSTRACT: Reactive Oxygen Species (ROS) production is one of the main mechanisms used to kill microbes during the innate immune response. D-lactic acid, which is augmented during acute ruminal acidosis, reduces platelet activating factor (PAF)-induced ROS production and L-selectin shedding in bovine neutrophils in vitro. This study was conducted to investigate whether acute ruminal acidosis induced by an acute oligofructose overload in heifers interferes with the ROS production and L-selectin shedding in blood neutrophils. Blood neutrophils and plasma were obtained by jugular venipuncture and ruminal samples were collected using rumenocentesis. Lactic acid from plasma and ruminal samples was measured by HPLC. PAF-induced ROS production and L-selectin shedding were measured in vitro in bovine neutrophils by a luminol chemiluminescence assay and by flow cytometry, respectively. A significant increase in ruminal and plasma lactic acid was recorded in these animals. Specifically, a decrease in PAF-induced ROS production was observed 8 h after oligofructose overload, and this was sustained until 48 h post oligofructose overload. A reduction in PAF-induced L-selectin shedding was observed at 16 h and 32 h post oligofructose overload. We concluded that neutrophil PAF responses were altered in heifers with ruminal acidosis, suggesting a potential dysfunction of the innate immune response.
    Journal of veterinary science (Suwŏn-si, Korea) 03/2014; 15(2). DOI:10.4142/jvs.2014.15.2.217 · 1.16 Impact Factor
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