Double-stranded RNA induces sickle erythrocyte adherence to endothelium: A potential role for viral infection in vaso-occlusive pain episodes in sickle cell anemia

Academic Article

Abstract

  • Vaso-occlusive pain episodes in sickle cell anemia are hypothesized to be precipitated by adherence of sickle erythrocytes to vascular endothelium in the microcirculation. Febrile episodes, thought to be viral in etiology, are frequently associated with vaso-occlusion; however, a direct link between viral infection and vascular occlusion has not yet been established. Many pathogenic viruses contain double-stranded RNA or replicate through double- stranded RNA intermediates. Double-stranded RNA has been shown to induce vascular cell adhesion molecule-1 (VCAM-1) protein expression on endothelial cells. Recently, a new adhesion pathway has been described between VCAM-1 expressed on cytokine stimulated endothelium and the α4β1 integrin complex expressed on sickle reticulocytes. Based on these observations, the hypothesis was developed that vital infection, through double-stranded RNA intermediates, increases endothelial VCAM-1 expression leading to sickle erythrocyte adhesion to endothelium via an α4β1-VCAM-1-dependent mechanism. In support of this hypothesis, endothelial cells exposed to the synthetic double-stranded RNA poly(I:C) or the RNA virus parainfluenza 1 (Sendai virus) express increased levels of VCAM-1 and support increased sickle erythrocyte adherence under continuous flow at 1.0 dyne/cm2 shear stress as compared with unstimulated endothelium. Blocking antibodies directed against either VCAM-1 on the endothelium or α4β1 on sickle erythrocytes inhibit nearly all of the increased sickle cell adherence caused by poly(I:C) or Sendai virus. These results support the hypothesis that viruses, through double-stranded RNA elements, can induce sickle erythrocyte adherence to endothelium through α4β1-VCAM-1-mediated adhesion and provide a potential link between viral infection and microvascular occlusion precipitating sickle cell pain episodes.
  • Published In

  • Blood  Journal
  • Author List

  • Smolinski PA; Offermann MK; Eckman JR; Wick TM
  • Start Page

  • 2945
  • End Page

  • 2950
  • Volume

  • 85
  • Issue

  • 10