Activation of sickle red blood cell adhesion via integrin-associated protein/CD47–induced signal transduction
Julia E. Brittain, … , Eugene P. Orringer, Leslie V. Parise
Julia E. Brittain, … , Eugene P. Orringer, Leslie V. Parise
Published June 15, 2001
Citation Information: J Clin Invest. 2001;107(12):1555-1562. https://doi.org/10.1172/JCI10817.
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Article

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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The low-density (reticulocyte-enriched) fraction of SS RBCs is most resp...
The low-density (reticulocyte-enriched) fraction of SS RBCs is most responsive to IAP stimulation. (a) Reticulocyte-enriched fractions of SS RBCs from two patients were prepared by centrifuging washed SS RBC over an arabinogalactan gradient (Larex Inc., White Bear Lake, New Jersey, USA) (74,000 g, 20°C, 45 minutes). SS RBCs collected from low- and high-density fractions were resuspended in perfusion media and packed at 400 g. A 1% hematocrit of each fraction was prepared, treated with or without 50 μM 4N1K peptide, and flowed over immobilized TSP. (b) AA reticulocytes respond to 4N1K stimulation. Washed RBCs from a patient with a hemolytic anemia and increased reticulocyte count were treated with 50 μM 4N1K agonist, 50 μM control 4NGG peptide, or 2 nM soluble TSP and flowed over immobilized TSP. Data are presented ± SD (n = 2 experiments) and are expressed in both panels as adherent cells per square millimeter.