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Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow

Vasilios A. Morikis, Shannon Chase, Ted Wun, Elliot L. Chaikof, John L. Magnani and Scott I. Simon

Key Points

  • Neutrophils rolling on E-selectin form catch-bonds with L-selectin that mechanosignal β2-integrin bond formation with intracellular adhesion molecule 1.

  • Rivipansel blocks E-selectin recognition of sLex on L-selectin, thereby antagonizing outside-in signaling of high-affinity β2-integrin.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

E-selectin extends from the plasma membrane of inflamed endothelium and serves to capture leukocytes from flowing blood via long-lived catch-bonds that support slow leukocyte rolling under shear stress. Its ligands are glycosylated with the tetrasaccharide sialyl Lewisx (sLex), which contributes to bond affinity and specificity. E-selectin-mediated rolling transmits signals into neutrophils that trigger activation of high-affinity β2-integrins necessary for transition to shear-resistant adhesion and transendothelial migration. Rivipansel is a glycomimetic drug that inhibits E-selectin-mediated vaso-occlusion induced by integrin-dependent sickle–red blood cell–leukocyte adhesion. How Rivipansel antagonizes ligand recognition by E-selectin and blocks outside-in signaling of integrin-mediated neutrophil arrest while maintaining rolling immune-surveillance is unknown. Here, we demonstrate that sLex expressed on human L-selectin is preferentially bound by E-selectin and, on ligation, initiates secretion of MRP8/14 that binds TLR4 to elicit the extension of β2-integrin to an intermediate affinity state. Neutrophil rolling over E-selectin at precise shear stress transmits tension and catch-bond formation with L-selectin via sLex, resulting in focal clusters that deliver a distinct signal to upshift β2-integrins to a high-affinity state. Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended β2-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium.

  • Submitted May 5, 2017.
  • Accepted August 3, 2017.
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