Abnormal adhesion and cell-cell interactions in sickle cell disease

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)

InsermInsermU665U665

Mohandas & Evans, Blood 1984

Abnormal adhesion of SS-RBC to the endothelium


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


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


α4β1 integrin

Lu/BCAM

Endothelial cells


Adhesion

Epinephrine

cAMP

PKA

Stress

VCAM-1



β2-AR

Lu/BCAM

Sickle Red

Blood Cell



α4β1 integrin


Lu/BCAM

Endothelial cells


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


?

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


?

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


α4β1 integrin


Sickle Red

Blood Cell

PBMC

Lu/BCAM

Endothelial cells

VCAM-1

Lu/BCAM


α4β1 integrin


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


α4β1 integrin


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

Neutrophils are key cellular components of the vasoocclusive process

Manwani & Frenette, Blood 2013

InsermU665

Cell-cell interactions: a key element targetting vasoocclusion

InsermU665


RBC

RBC

RBC

Labie & Elion, Hématologie

InsermU665


RBC

RBC

RBC

endotheliumLabie & Elion, Hématologie

InsermU665


RBC

RBC

RBC

Procoagulant status


InsermU665


RBC

RBC

RBC

Procoagulant status


Proinflammatory and prooxidativeenvironment

InsermU665


neutrophilsRBC

RBC

RBC

Procoagulant status



InsermU665


RBC

RBC

RBC

Procoagulant status

endothelium

Global cell activationLabie & Elion, Hématologie


InsermU665


neutrophilsRBC

RBC

RBC

Procoagulant status

endothelium

Global cell activation microparticlesLabie & Elion, Hématologie


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


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


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


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

Abnormal adhesion and cell-cell interactions in sickle cell disease

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