Activation of sickle red blood cell adhesion via integrin-associated protein/CD47–induced signal transduction
Julia E. Brittain, Kathryn J. Mlinar, Christopher S. Anderson, Eugene P. Orringer, Leslie V. Parise
Julia E. Brittain, Kathryn J. Mlinar, Christopher S. Anderson, Eugene P. Orringer, Leslie V. Parise
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Activation of sickle red blood cell adhesion via integrin-associated protein/CD47–induced signal transduction

Abstract

Peripheral human red blood cells (RBCs) are not generally known to become activated and adhesive in response to cell signaling. We show, however, that soluble thrombospondin via integrin-associated protein (IAP; CD47) increases the adhesiveness of sickle RBCs (SS RBCs) by activating signal transduction in the SS RBC. This stimulated adhesion requires occupancy of IAP and shear stress and is mediated by the activation of large G proteins and tyrosine kinases. Reticulocyte-enriched RBCs derived from sickle-cell disease (SCD) patients are most responsive to IAP-induced activation. These studies therefore establish peripheral SS RBCs as signaling cells that respond to a novel synergy between IAP-induced signal transduction and shear stress, suggesting new therapeutic targets in SCD.

Authors

Julia E. Brittain, Kathryn J. Mlinar, Christopher S. Anderson, Eugene P. Orringer, Leslie V. Parise

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IAP-induced adhesion of SS RBCs requires Gi and tyrosine kinase activity...
IAP-induced adhesion of SS RBCs requires Gi and tyrosine kinase activity. (a) SS RBC adhesion to immobilized TSP under flow conditions, stimulated by a submaximal concentration of agonist peptide 4N1K (16 μM), is completely blocked by pretreatment (30 minutes) with the large G protein inhibitor pertussis toxin (1 μg/ml) or the tyrosine kinase inhibitors genistein (260 μM) or piceatannol (30 μg/ml). (b) SS RBC adhesion to immobilized TSP that is stimulated by a submaximal concentration of soluble TSP (2 nM) is partially blocked by preincubation with pertussis toxin (1 μg/ml) and completely blocked with genistein. Normalized data with basal adhesion subtracted out represent four 4N1K- and two TSP-treated patient samples, respectively (± SD).