title: E-selectin ligands as mechanosensitive receptors on neutrophils in health and disease.
abstract: Application of mechanical force to bonds between selectins and their ligands is a requirement for these adhesion receptors to optimally perform functions that include leukocyte tethering and activation of stable adhesion. Although all three selectins are reported to signal from the outside-in subsequent to ligand binding, E-selectin is unique in its capacity to bind multiple sialyl Lewis x presenting ligands and mediate slow rolling on the order of a micron per second. A diverse set of ligands are recognized by E-selectin in the mouse, including ESL-1, CD44 (HCELL), and PSGL-1 which are critical in transition from slow rolling to arrest and for efficient transendothelial migration. The molecular recognition process is different in humans as L-selectin is a major ligand, which along with glycolipids constitute more than half of the E-selectin receptors on human polymorphonuclear neutrophils (PMN). In addition, E-selectin is most efficient at raising the affinity and avidity of CD18 integrins that supports PMN deceleration and trafficking to sites of acute inflammation. The mechanism is only partially understood but known to involve a rise in cytosolic calcium and tyrosine phosphorylation that activates p38 MAP kinase and Syk kinase, both of which transduce signals from clustered E-selectin ligands. In this review we highlight the molecular recognition and mechanical requirements of this process to reveal how E-selectin confers selectivity and efficiency of signaling for extravasation at sites of inflammation and the mechanism of action of a new glycomimetic antagonist targeted to the lectin domain that has shown efficacy in blocking neutrophil activation and adhesion on inflamed endothelium.
authors.affiliation: University of California Davis, Davis, CA, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Chase
authors.forename: J L
authors.initials: JL
authors.lastname: Magnani
authors.forename: S I
authors.initials: SI
authors.lastname: Simon
mesh_terms: D000208:Acute Disease; D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D057705:Transendothelial and Transepithelial Migration; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D002118:Calcium; D019040:E-Selectin; D018960:Hyaluronan Receptors; D008024:Ligands; D008562:Membrane Glycoproteins; D048051:p38 Mitogen-Activated Protein Kinases; C084882:P-selectin ligand protein; C546936:SELE protein, human; C497483:CD44 protein, human