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Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2478-2488
Oxidative stress activates red cell adhesion to laminin in sickle cell disease
Maria Alejandra Lizarralde-Iragorri,1,2,3* Sophie D. Lefevre,1,2,3*
Sylvie Cochet,1,2,3 Sara El Hoss,1,2,3 Valentine Brousse,1,2,3,4 Anne Filipe,1,2,3.5 Michael Dussiot,6 Slim Azouzi,1,2,3 Caroline Le Van Kim,1,2,3
Fernando Rodrigues-Lima,5 Olivier Français,7 Bruno Le Pioufle,8 Thomas Klei,9 Robin van Bruggen9 and Wassim El Nemer1,2,3
*MALI and SDL contributed equally as co-first authors.
1Université de Paris, UMR S1134, BIGR, INSERM, Paris, France; 2Institut National de la Transfusion Sanguine, Paris, France; 3Laboratoire d’Excellence GR-Ex, Paris, France; 4Service de Pédiatrie Générale et Maladies Infectieuses, Hôpital Universitaire Necker Enfants Malades, Paris, France; 5Université de Paris, BFA, UMR 8251, CNRS, Paris, France; 6Institut Imagine, INSERM U1163, CNRS UMR8254, Université Paris Descartes, Hôpital Necker Enfants Malades, Paris, France; 7ESYCOM, Université Gustave Eiffel, CNRS UMR 9007, ESIEE Paris, Marne-la-Vallee, France; 8Université Paris-Saclay, ENS Paris-Saclay, CNRS Institut d'Alembert, LUMIN, Gif sur Yvette, France and 9Department of Blood Cell Research, Sanquin Research and Lab Services and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
ABSTRACT
Vaso-occlusive crises are the hallmark of sickle cell disease (SCD). They are believed to occur in two steps, starting with adhesion of deformable low-dense red blood cells (RBC), or other blood cells such as neutrophils, to the wall of post-capillary venules, followed by trapping of denser RBC or leukocytes in the areas of adhesion because of reduced effective lumen-diameter. In SCD, RBC are heterogeneous in terms of density, shape, deformability and surface proteins, which accounts for the differences observed in their adhesion and resistance to shear stress. Sickle RBC exhibit abnormal adhesion to laminin mediated by Lu/BCAM protein at their surface. This adhesion is triggered by Lu/BCAM phosphorylation in reticulocytes but such phosphorylation does not occur in mature dense RBC despite firm adhesion to laminin. In this study, we investigated the adhesive properties of sickle RBC sub- populations and addressed the molecular mechanism responsible for the increased adhesion of dense RBC to laminin in the absence of Lu/BCAM phosphorylation. We provide evidence for the implication of oxidative stress in post-translational modifications of Lu/BCAM that impact its distribution and cis-interaction with glycophorin C at the cell surface activating its adhesive function in sickle dense RBC.
Introduction
Sickle cell disease (SCD) is an autosomal recessive disorder caused by a single mutation in the sixth codon of the β-globin gene resulting in the expression of an abnormal hemoglobin that polymerizes under hypoxic conditions driving red blood cell (RBC) sickling.1 SCD is a multisystem disease characterized by hemolyt- ic anemia, recurrent painful vaso-occlusive crises (VOC), stroke, acute chest syn- drome, organ failure and high susceptibility to infections.2,3 On the cellular level, SCD is characterized by dehydration and RBC sickling, which decrease cell deformability and increase rigidity resulting in altered blood rheology and micro- circulatory flow.2-6 In addition, RBC are known to be highly adhesive in SCD.7-9 This abnormal adhesion to the endothelium is a contributing factor of the VOC and is believed to be triggered by signaling cascades that activate adhesion proteins at the red cell surface.10 A two-step model, based on in vivo vaso-occlusion obser- vations in SCD mouse models, postulates that adhesion of deformable low-dense RBC and stress reticulocytes reduces effective lumen-diameter of post-capillary venules promoting selective trapping of the denser and misshapen RBC in the areas
Red Cell Biology & its Disorders
Correspondence:
WASSIM EL NEMER
wassim.el-nemer@efs.sante.fr
Received: June 2, 2020. Accepted: August 12, 2020. Pre-published: August 27, 2020.
https://doi.org/10.3324/haematol.2020.261586 ©2021 Ferrata Storti Foundation
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