Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow.
Blood
; 130(19): 2101-2110, 2017 11 09.
Article
en En
| MEDLINE
| ID: mdl-28811304
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 ß2-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 ß2-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 ß2-integrins to a high-affinity state. Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended ß2-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Inhibición de Migración Celular
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Endotelio Vascular
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Antígenos CD18
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Selectina L
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Selectina E
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Mecanotransducción Celular
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Rodamiento de Leucocito
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Migración Transendotelial y Transepitelial
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Anemia de Células Falciformes
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Neutrófilos
Límite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Blood
Año:
2017
Tipo del documento:
Article
País de afiliación:
Canadá