Abstract
L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLex) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.
Highlights
King’s College London, School of Cardiovascular Medicine and Sciences, BHF Center of Research Excellence, London, United Kingdom
Since its identification and characterization, the expression of Lselectin has been carefully interrogated in numerous leukocyte subsets
A major unanswered question in many such immune cell subsets is to understand if there is a direct role for L-selectin signaling in bestowing their unique functionality
Summary
Over-expression of these variants in cells lacking L-selectin reveal altered capacities in adhesion to sLex under flow, ectodomain shedding in response to cellular activation, and signaling to p38 MAPK following antibody-mediated clustering (AMC) [11]. The first in vitro transmigration experiments involved the addition of primary human neutrophil suspensions onto cytokine-activated monolayers of human umbilical vein endothelial cells (HUVEC) In such assays, L-selectin is rapidly cleared from the neutrophil plasma membrane through ectodomain shedding [72]. Neutrophils aspirated from the fluid of acutely formed skin blisters were shown to be primed (e.g., CD11bpositive) and L-selectin-negative These observations suggest that the mechanisms of neutrophil migration toward acute or chronic inflammation could differ in the expression and turnover of adhesion molecules.
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