Journal
BLOOD
Volume 130, Issue 19, Pages 2101-2110Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-05-783027
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Funding
- National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases [2R01AI047294]
- NIH, National Institute of Diabetes and Digestive and Kidney Diseases [R01DK107405]
- NIH, National Institute of General Medical Sciences [U01GM116196]
- NIH, National Heart, Lung, and Blood Institute [R01HL128237]
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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 Lewis(x) (sLe(x)), which contributes to bond affinity and specificity. E-selectin mediated rolling transmits signals into neutrophils that trigger activation of high-affinity beta(2)-integrins necessary for transition to shear-resistant adhesion and transendothelial migration. Rivipansel is a glycomimetic drug that inhibits E-selectin-mediated vasoocclusion 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, wedemonstrate 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 beta(2)-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 beta(2)-integrins to a high-affinity state. Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended beta(2)-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium.
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