Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion (original) (raw)
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Erythroid adhesion molecules in sickle cell disease: Effect of hydroxyurea
Transfus Clin Biol, 2008
In sickle cell disease, the complex scenario of vaso-occlusive crisis (VOC) typical of this disease is clearly multifactorial and not fully understood. Cell-cell and cell-cell matrix interactions mediated by adhesive molecules present on blood cells and endothelial cells (ECs) are thought to play an important role. Early studies have shown that sickle red blood cells (RBCs) are abnormally adherent to ECs and some of the molecules involved in these interactions have been identified, such as the a4b1 integrin and CD36, exclusively present on stress reticulocytes, and CD47 on mature RBCs. More recently, attention focused on Lu/BCAM, the unique RBC receptor for laminin, and on ICAM-4, a red cell-specific adhesion receptor, which is a ligand for a large repertoire of integrins (aLb2, aMb2, axb2, aVb3). The counter-receptors on ECs and the role of plasma proteins forming bridges between blood cells and ECs have been clarified in part. It has also been shown that reticulocytes from SCD patients express higher levels of a4b1 integrin and CD36, and that under hydroxyurea (HU) therapy, both cell adhesion to ECs or extracellular matrix proteins and the levels of these adhesion molecules are reduced. These findings are consistent with the view that enhanced adhesion of blood cells to ECs is largely determined by the membrane expression level of adhesion molecules and could be a crucial factor for triggering or aggravating vaso-occlusion. In SCD patients, membrane expression of Lu/BCAM (and perhaps ICAM-4) is enhanced on RBCs whose adherence to laminin or ECs is also increased. Interestingly, Lu/BCAM- and ICAM-4-mediated adhesion are enhanced by the stress mediator epinephrine through a PKA-dependent pathway initiated by a rise in intracellular cAMP and leading to receptor activation by phosphorylation according to the same signaling pathway. More recently, studies based on quantitative expression analysis of adhesion molecules on RBCs and during erythroid differentiation in patients undergoing HU therapy, surprisingly revealed that Lu/BCAM level was enhanced, although a4b1, CD36 and ICAM-4 (to a lower extent) levels were indeed reduced. CD47 and CD147 expression were also enhanced in HU-treated patients. Based on these findings we suggest that the signalization cascade leading to receptor activation rather than the expression level only of adhesion molecules may be the critical factor regulating cell adhesion, although both mechanisms are not mutually exclusive.
Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo
Blood, 2007
Sickle red cell (SS RBC) adhesion is believed to contribute to the process of vaso-occlusion in sickle cell disease (SCD). We previously found that the LW RBC adhesion receptor can be activated by epinephrine to mediate SS RBC adhesion to endothelial αvβ3 integrin. To determine the contribution of LW activation to vaso-occlusive events in vivo, we investigated whether in vitro treatment of SS RBCs by epinephrine resulted in vaso-occlusion in intact microvasculature after RBC infusion into nude mice. Epinephrine enhanced human SS but not normal RBC adhesion to murine endothelial cells in vitro and to endothelium in vivo, promoting vaso-occlusion and RBC organ sequestration. Murine sickle RBCs also responded to epinephrine with increased adhesion to postcapillary endothelium in nude mice. Epinephrine-induced SS RBC adhesion, vaso-occlusion, and RBC organ trapping could be prevented by the β-adrenergic receptor (β-AR) antagonist, propranolol. Infusion of soluble recombinant LW also sig...
In sickle cell disease, the complex scenario of vaso-occlusive crisis (VOC) typical of this disease is clearly multifactorial and not fully understood. Cell-cell and cell-cell matrix interactions mediated by adhesive molecules present on blood cells and endothelial cells (ECs) are thought to play an important role. Early studies have shown that sickle red blood cells (RBCs) are abnormally adherent to ECs and some of the molecules involved in these interactions have been identified, such as the a4b1 integrin and CD36, exclusively present on stress reticulocytes, and CD47 on mature RBCs. More recently, attention focused on Lu/BCAM, the unique RBC receptor for laminin, and on ICAM-4, a red cell-specific adhesion receptor, which is a ligand for a large repertoire of integrins (a L b 2 , a M b 2 , a x b 2 , a V b 3). The counter-receptors on ECs and the role of plasma proteins forming bridges between blood cells and ECs have been clarified in part. It has also been shown that reticulocytes from SCD patients express higher levels of a4b1 integrin and CD36, and that under hydroxyurea (HU) therapy, both cell adhesion to ECs or extracellular matrix proteins and the levels of these adhesion molecules are reduced. These findings are consistent with the view that enhanced adhesion of blood cells to ECs is largely determined by the membrane expression level of adhesion molecules and could be a crucial factor for triggering or aggravating vaso-occlusion. In SCD patients, membrane expression of Lu/BCAM (and perhaps ICAM-4) is enhanced on RBCs whose adherence to laminin or ECs is also increased. Interestingly, Lu/BCAM-and ICAM-4-mediated adhesion are enhanced by the stress mediator epinephrine through a PKA-dependent pathway initiated by a rise in intracellular cAMP and leading to receptor activation by phosphorylation according to the same signaling pathway. More recently, studies based on quantitative expression analysis of adhesion molecules on RBCs and during erythroid differentiation in patients undergoing HU therapy, surprisingly revealed that Lu/BCAM level was enhanced, although a4b1, CD36 and ICAM-4 (to a lower extent) levels were indeed reduced. CD47 and CD147 expression were also enhanced in HU-treated patients. Based on these findings we suggest that the signalization cascade leading to receptor activation rather than the expression level only of adhesion molecules may be the critical factor regulating cell adhesion, although both mechanisms are not mutually exclusive. Résumé Dans la drépanocytose, la survenue des crises vaso-occlusives est un scénario multifactoriel très complexe qui reste encore mal compris. Des interactions cellules-cellules et cellules-protéines de la matrice extracellulaire régulées par des molécules d'adhérence présentes sur les cellules sanguines et les cellules endothéliales (CEs) semblent jouer un rôle important. Des études anciennes ont montré que les globules rouges drépanocytaires adhèrent anormalement à l'endothélium vasculaire et certaines molécules impliquées dans ces interactions ont été identifiées, par exemple l'intégrine a4b1 et le CD36, qui sont exprimées exclusivement sur les réticulocytes, et le CD47 présent sur les globules rouges matures. Plus récemment, l'attention s'est portée sur Lu/BCAM, l'unique récepteur de la laminine présent sur les globules rouges, et sur ICAM-4, un récepteur d'adhérence spécifique des globules rouges, ligand d'un vaste répertoire d'intégrines (a L b 2 , a M b 2 , a x b 2 , a V b 3). Les contre-récepteurs sur les CEs et le rôle de protéines plasmatiques formant des ponts intercellulaires entre cellules sanguines et les CEs ont été clarifiés en partie. Il a