Abnormal adhesion and cell-cell interactions in sickle cell disease
Jacques Elion, MD, PhDFrench National Reference Centers for Sickle Cell Disease
Department of Medical Genetics and Inserm UMR 665 – INTS
Robert Debré Mother and Child University Hospital, 75019 Paris, FranceGuadeloupe University Hospital, 97139 Les Abymes (French West Indies)
Laboratory of Excellence on the Red Cell – GR-Ex
The primary pathophysiological event of SCD is insufficient to explain vasoocclusion since the delay time to HbS polymerizationis longer than the time required in the circulation to reoxygenate the blood.
Thus all mechanisms reducingblood flow may constitute a triggering factor
…. cell adhesion…. vascular tone
Steinberg M.H., N Engl J Med 1999; 340:1021-1030
Vasoocclusive crises the hallmarkof Sickle Cell Disease (SCD)
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Mohandas & Evans, Blood 1984
Abnormal adhesion of SS-RBC to the endothelium
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Hoover R, Rubin R, Wise G, Warren R Adhesion of normal and sickle erythrocytes to endothelial monolayer cultures.Blood 1979, 54:872-876
Hebbel RP, Yamada O, Moldow CF, Jacob HS, White JG, Eaton JWAbnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease.J Clin Invest 1980, 65:154-160
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Circulating stress reticulocytes express two pro-adhesion molecules normally found on erythroid precusors in the bone marrow
Elion & LabieHématologie 1998
(α4β1 integrin)
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Subendothelial laminin α5
α4β1 integrin
Lu/BCAM
Endothelial cells
RBC adhesion to the vascular wall is a multimolecular complex phenomenon
VCAM-1
El Nemer et al, Blood 2007
Gauthier et al, J Biol Chem 2005
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Subendothelial laminin α5
α4β1 integrin
Lu/BCAM
Endothelial cells
RBC adhesion to the vascular wall is a multimolecular complex phenomenon
Adhesion
Epinephrine
cAMP
PKA
Stress
VCAM-1
El Nemer et al, Blood 2007
Gauthier et al, J Biol Chem 2005
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Gauthier et al, J Biol Chem 2005
Subendothelial laminin α5
α4β1 integrin
El Nemer et al, Blood 2007
Lu/BCAM
Endothelial cells
RBC adhesion to the vascular wall is a multimolecular complex phenomenon
Adhesion
cAMP
PKA
Stress
VCAM-1Abnormal cell-cell interactions in SCD are triggered by cell activation via signalling events
Epinephrine
Sickle reticulocyte
DARC(Duffy Antigen)
VCAM-1
Endothelial cells Fibronectin
RBC activation involves several stimuli, partners, and mechanisms
InsermU665
α4β1 integrin
Sickle reticulocyte
DARC(Duffy Antigen)
IL-8 RANTES
VCAM-1
Endothelial cells
α4β1 integrin
Fibronectin
RBC activation involves several stimuli, partners, and mechanisms
?
Adhesion
InsermU665
Durpes et al, J Biol Chem 2011
Sickle reticulocyte
DARC(Duffy Antigen)
IL-8 RANTES
Durpes et al, J Biol Chem 2011VCAM-1
Endothelial cells
α4β1 integrin
Fibronectin
RBC activation involves several stimuli, partners, and mechanisms
?
Adhesion
InsermU665
Inflammatory chemokines are capable of activating RBC adhesion through a cross-talk between DARC and the α4β1 integrin
SS-RBC interacts with mononuclear cells
Chaar et al, Haematological 2010
Imaging flow cytometry
InsermU665
Sickle Red
Blood Cell
Lu/BCAM
Endothelial cells
VCAM-1
Lu/BCAM
Subendothelial laminin α5
α4β1 integrin
SS-RBC interacts with mononuclear cells
Sickle Red
Blood Cell
PBMC
Lu/BCAM
Endothelial cells
VCAM-1
Lu/BCAM
Subendothelial laminin α5
α4β1 integrin
SS-RBC interacts with mononuclear cells
Chaar et al, Haematologica 2010
Sickle Red
Blood Cell
PBMC
Chaar et al, Haematologica 2010
α4β1 integrin
Lu/BCAM
Lu/BCAM
Endothelial cells
VCAM-1
Lu/BCAM
Subendothelial laminin α5
α4β1 integrin
SS-RBC interacts with mononuclear cells
Abnormal cell-cell interactions in SCD is a highly complex phenomenoninvolving multiple cellular and molecular partners
from JP Cartron SCADHESION project C Le Van Kim, PL Tharaux, J Elion InsermUMR 665
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
RBC
RBC
RBC
Labie & Elion, Hématologie
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
RBC
RBC
RBC
endotheliumLabie & Elion, Hématologie
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
RBC
RBC
RBC
Procoagulant status
endotheliumLabie & Elion, Hématologie
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
RBC
RBC
RBC
Procoagulant status
endotheliumLabie & Elion, Hématologie
Proinflammatory and prooxidativeenvironment
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
neutrophilsRBC
RBC
RBC
Procoagulant status
endotheliumLabie & Elion, Hématologie
Proinflammatory and prooxidativeenvironment
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
RBC
RBC
RBC
Procoagulant status
endothelium
Global cell activationLabie & Elion, Hématologie
Proinflammatory and prooxidativeenvironment
InsermU665
Cell-cell interactions: a key element targetting vasoocclusion
neutrophilsRBC
RBC
RBC
Procoagulant status
endothelium
Global cell activation microparticlesLabie & Elion, Hématologie
Proinflammatory and prooxidativeenvironment
Ware, Blood 2010; 115:5300-5311
Interestingly, hydroxycarbamide (hydroxyurea) is a pleiotropic agent that also modulates cell-cell interactions
InsermU665
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Laminin α5
Epinephrine
cAMP
α4β1 integrin
Lu/BCAM
Endothelial cells
PBMC
PKA
α4β1 integrin
Lu/BCAM
Effect of HC on cell-cell interactions in SCD
InsermU665
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Laminin α5
Epinephrine
cAMP
α4β1 integrin
Lu/BCAM
Endothelial cells
PBMC
PKA
α4β1 integrin
Lu/BCAM
HCLess aggregation
Effect of HC on cell-cell interactions in SCD
InsermU665
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Laminin α5
Epinephrine
α4β1 integrin
Lu/BCAM
Endothelial cells
PBMC
PKA
α4β1 integrin
Lu/BCAM
HCLess aggregation
Effect of HC on cell-cell interactions in SCD
Odièvre et al, Haematologica2008Bartolucci et al, Blood 2010
Less adhesion
cAMP
InsermU665
β2-AR
Lu/BCAM
Sickle Red
Blood Cell
Laminin α5
Epinephrine
α4β1 integrin
Lu/BCAM
Endothelial cells
PBMC
PKA
α4β1 integrin
Lu/BCAM
HCLess aggregation
Effect of HC on cell-cell interactions in SCD
Odièvre et al, Haematologica2008Bartolucci et al, Blood 2010
Less adhesion
cAMP
HC diminishes cell adhesion by inhibiting Lu/BCAM phosphorylation, independently of its expression level
InsermU665
Conclusion
Cell-cell interactions are key elements of the pathophysiology of SCD
Better understanding of their complex and intricatemechanisms is mandatory to identify new potentialtherapeutic targets
SCD Reference Center,French Antilles and Guiana
Marie-Dominique Hardy DessourcesMarie-Claude DurpesMonique DecatelMarc RomanaNathalie LemonneDanitza Nebor
Inserm UMR 665and
SCD Reference Center, Paris
Jacques Elion Emilie GauthierWassim El NemerJulien PicotVicky ChaarPablo BartolucciClaudine LapouméroulieMarie-Hélène OdièvreMalika BenkerrouCaroline Le Van KimYves Colin
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