E-selectin ligands as mechanosensitive receptors on neutrophils in health and disease

S. D. Chase, J. L. Magnani, S. I. Simon

Research output: Contribution to journalArticle

39 Scopus citations

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 polymorpho-nuclear 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.

Original languageEnglish (US)
Pages (from-to)849-859
Number of pages11
JournalAnnals of Biomedical Engineering
Volume40
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • Cell signaling
  • E-selectin
  • L-selectin
  • Neutrophils
  • PSGL-1

ASJC Scopus subject areas

  • Biomedical Engineering

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