References of "Oury, Cécile"
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See detailCLEC-2 is required for the activation of mouseplatelets by bacterial DNA mimetics
Delierneux, Céline ULiege; Hego, Alexandre ULiege; LECUT, Christelle ULiege et al

Conference (2015, June 22)

Background: Short nuclease-resistant phosphorothioate synthetic CpG motif-bearing oligonucleotides (CpG ODNs) mimicking bacterial DNA display potent immunostimulatory activity and are therefore being used ... [more ▼]

Background: Short nuclease-resistant phosphorothioate synthetic CpG motif-bearing oligonucleotides (CpG ODNs) mimicking bacterial DNA display potent immunostimulatory activity and are therefore being used in clinical trials as vaccine adjuvants. Cellular uptake and activation depends on the interaction of CpG ODNs with the C-type lectin receptor DEC-205 and subsequent stimulation of the Toll-like receptor 9 (TLR9) and myeloid differentiation primary response 88 (MyD88) signaling cascade. Platelets express TLR9, MyD88, and the C-type lectin-like receptor 2 (CLEC-2). However, the impacts of CpG ODNs on platelet function have been elusive. Aims: To evaluate whether CpG ODNs affect platelet activation and thrombus formation via CLEC-2 and TLR9. Methods: We incubated washed platelets or whole blood from TLR9-, MyD88- or CLEC-2- deficient mice with CpG ODNs. We performed platelet aggregometry, flow cytometric binding and platelet activation assays as well as signal transduction analyses. Thrombus formation and fibrin generation were also analyzed by intravital microscopy in mouse microcirculation upon intravenous injection of CpG ODNs. Results: We show that CpG ODNs bind on platelet surface and are internalized. They activate platelets and induce their aggregation. TLR9- or MyD88-deficient platelets aggregated normally in response to CpG ODN. Interestingly, platelets deficient for the C-type lectin receptor CLEC-2 were unable to capture and internalize CpG ODN. CLEC-2 deficiencyabolished CpG ODN-induced platelet activation and aggregation. CpG ODN stimulated CLEC-2 dependent tyrosine kinase pathway and Syk phosphorylation. In vivo, intravenously injected CpG ODN interacted with platelets adhered to laser injured arteriolar endothelia and promoted fibrin generation and thrombus growth. Conclusion: CLEC-2 mediates CpG ODN uptake and subsequent platelet activation, independently of TLR9, which may serve an important role in the interplay between platelets and immunity. [less ▲]

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See detailCLEC-2 is required for the activation of mouse platelets by bacterial DNA mimetics
Delierneux, Céline ULiege; Hego, Alexandre ULiege; LECUT, Christelle ULiege et al

Conference (2015, June 22)

Aims: To evaluate whether CpG ODNs affect platelet activation and thrombus formation via CLEC-2 and TLR9. Methods: We incubated washed platelets or whole blood from TLR9-, MyD88- or CLEC-2- deficient mice ... [more ▼]

Aims: To evaluate whether CpG ODNs affect platelet activation and thrombus formation via CLEC-2 and TLR9. Methods: We incubated washed platelets or whole blood from TLR9-, MyD88- or CLEC-2- deficient mice with CpG ODNs. We performed platelet aggregometry, flow cytometric binding and platelet activation assays as well as signal transduction analyses. Thrombus formation and fibrin generation were also analyzed by intravital microscopy in mouse microcirculation upon intravenous injection of CpG ODNs. Results: We show that CpG ODNs bind on platelet surface and are internalized. They activate platelets and induce their aggregation. TLR9- or MyD88-deficient platelets aggregated normally in response to CpG ODN. Interestingly, platelets deficient for the C-type lectin receptor CLEC-2 were unable to capture and internalize CpG ODN. CLEC-2 deficiency abolished CpG ODN-induced platelet activation and aggregation. CpG ODN stimulated CLEC-2 dependent tyrosine kinase pathway and Syk phosphorylation. In vivo, intravenously injected CpG ODN interacted with platelets adhered to laser injured arteriolar endothelia and promoted fibrin generation and thrombus growth. Conclusion: CLEC-2 mediates CpG ODN uptake and subsequent platelet activation, independently of TLR9, which may serve an important role in the interplay between platelets and immunity. [less ▲]

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See detailHigh-dose oral intake of serotonin induces valvular heart disease in rabbits.
Lancellotti, Patrizio ULiege; NCHIMI LONGANG, Alain ULiege; Hego, Alexandre ULiege et al

in International Journal of Cardiology (2015), 197

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely ... [more ▼]

Carcinoid tumors are rare neuroendocrine malignancies, often originating from enterochromaffin cells in the gastrointestinal tract. They can secrete serotonin (5-hydroxytryptamine, 5-HT), which is largely inactivated by the liver. Carcinoid heart disease occurs when tumor cells metastasize to the liver, as the vasoactive substances produced are able to reach the systemic circulation via the hepatic vein, causing deposition of fibrous tissue on the endocardial surfaces of the heart. It is predominantly manifested by right-sided valvular heart disease (VHD). Scavenging enzymes in the pulmonary endothelium may explain why left-sided cardiac involvement is unusual. The severity of cardiac damage is correlated with the plasmatic levels of serotonin, but the lowspecificity of serotonin for cardiac damage suggests that serotonin may be necessary but not sufficient to induce cardiac lesions. Therefore, other factors combined with serotonin might be required to induce VHD. However, recent animal studies confirmed the development of carcinoid-like valvular deposits in rats after 3 months of daily subcutaneous/intraperitoneal serotonin injections to avoid the liver first-pass clearance.Whether oral administration of serotonin can also induce VHD is unknown. We hypothesized that long-term oral serotonin overload in rabbits can lead to VHD, mimicking serotonin-induced lesions of carcinoid heart disease. We demonstrate, for the first time that high dose long-term oral administration of serotonin can lead to VHD in rabbits. [less ▲]

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See detailPerspective: Tyrosine Phosphatases As Novel Targets For Antiplatelet Therapy
Tautz, Lutz; Senis, Yotis; Oury, Cécile ULiege et al

in Bioorganic & Medicinal Chemistry (2015), 23(12), 2786-97

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory ... [more ▼]

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy. [less ▲]

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See detailDUSP3 genetic deletion confers M2-like−macrophage-dependent tolerance to septic shock
Singh, Pratibha; Dejager, Lien; Amand, Mathieu ULiege et al

in Journal of Immunology (2015), 194(10), 4951-62

DUSP3 is a small dual-specificity protein phosphatase with an unknown physiological function. We report that DUSP3 is strongly expressed in human and mouse monocytes and macrophages and that its ... [more ▼]

DUSP3 is a small dual-specificity protein phosphatase with an unknown physiological function. We report that DUSP3 is strongly expressed in human and mouse monocytes and macrophages and that its deficiency in mice promotes tolerance to lipopolysaccharide (LPS)-induced endotoxin shock and to polymicrobial septic shock following cecal ligation and puncture. By using adoptive transfer experiments, we demonstrate that resistance to endotoxin is macrophage-dependent and transferable and that this protection is associated with a striking increase of M2-like macrophages in DUSP3-/- mice in both the LPS and cecal ligation and puncture models. We show that the altered response of DUSP3-/- mice to sepsis is reflected in decreased TNF production and impaired ERK1/2 activation. Our results demonstrate that DUSP3 plays a key and non-redundant role as a regulator of innate immune responses by mechanisms involving the control of ERK1/2 activation, TNF secretion and macrophage polarization. [less ▲]

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See detailEpithelial-to-Mesenchymal Transitions modulate interactions between Circulating Tumor Cells and the coagulation system: implication for the metastatic spread.
Bourcy, M; Suarez-Carmona, M; Francart, ME et al

Conference (2015, May 13)

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See detailReflections about the optimisation of the treatment of tendinopathies with PRP
Kaux, Jean-François ULiege; Bouvard, Marc; LECUT, Christelle ULiege et al

in Muscles, Ligaments and Tendons Journal (2015), 5(1 (eCollection 2015 Jan-Mar)), 1-4

Background: platelet-rich plasma (PRP) infiltration represents a recent therapy for chronic tendinopathies. However, in the literature, this treatment remains controversial. Purpose: we suggest some ideas ... [more ▼]

Background: platelet-rich plasma (PRP) infiltration represents a recent therapy for chronic tendinopathies. However, in the literature, this treatment remains controversial. Purpose: we suggest some ideas for improving this treatment. Methods: these suggestions were based on a review of published studies and our clinical experience. Conclusion: optimizing the technique for PRP collection is paramount. Different risk factors must be corrected before infiltration and chronic tendinopathies must be carefully selected. Finally, post-infiltration rehabilitation remains absolutely critical. Standardization of the use of PRP remains necessary in order to optimize the results. [less ▲]

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See detailDUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia ULiege; Kuijpers, Marijke; Gilio, Karen et al

in Circulation (2015), 131(7), 656-68

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet ... [more ▼]

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. [less ▲]

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See detailPurinergic control of inflammation and thrombosis: Role of P2X1 receptors
Oury, Cécile ULiege; LECUT, Christelle ULiege; Hego, Alexandre ULiege et al

in Computational and Structural Biotechnology Journal (2015), 13

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between ... [more ▼]

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In thismodel, by using P2X1−/−mice,we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1−/−mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation. [less ▲]

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See detailPositron Emission Tomography/Computed Tomography Imaging in Device Infective Endocarditis: Ready for Prime Time
Lancellotti, Patrizio ULiege; Habib, Gilbert; Oury, Cécile ULiege et al

in Circulation (2015), 132

Over the last decade there has been a remarkable increase in prosthetic heart valve replacement and cardiac implantable electronic device utilization. Although capable of improving the quality and ... [more ▼]

Over the last decade there has been a remarkable increase in prosthetic heart valve replacement and cardiac implantable electronic device utilization. Although capable of improving the quality and quantity of life of patients suffering from severe valvular heart disease or rhythm disorders, they are both subject to potentially life-threatening infection involving the endocardium, referred to as device infective endocarditis (DIE)1,2. The rate of prosthetic valve endocarditis (PVE) ranges from 1-6% to 15%, being higher in revision surgery1. The infection usually involves the junction between the sewing ring and the annulus, leading to perivalvular abscess, dehiscence, pseudo-aneurysms, and fistulae, or the leaflets of the prosthesis, leading to vegetations, cusp rupture, and perforation. Cardiac device-related infective endocarditis (CDRIE), to be distinguished from local device infection (pocket/generator), is defined as an infection involving the electrode leads, cardiac valve leaflets, or endocardial surface. An incidence of 1.4 per 1000 device-years of definite CDRIE has been reported3. DIE may occur at anytime, being related to surgery only in early cases. [less ▲]

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See detailElevated Plasma Soluble ST2 Is Associated with Heart Failure Symptoms and Outcome in Aortic Stenosis.
LANCELLOTTI, Patrizio ULiege; DULGHERU, Raluca Elena ULiege; Magne, Julien et al

in PloS one (2015), 10(9), 0138940

B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is ... [more ▼]

B-type natriuretic peptide (BNP) is often used as a complementary finding in the diagnostic work-up of patients with aortic stenosis (AS). Whether soluble ST2, a new biomarker of cardiac stretch, is associated with symptomatic status and outcome in asymptomatic AS is unknown. sST2 and BNP levels were measured in 86 patients (74+/-13 years; 59 asymptomatic, 69%) with AS (<1.5 cm2) and preserved left ventricular ejection fraction who were followed-up for 26+/-16 months. Both BNP and sST2 were associated with NYHA class but sST2 (>23 ng/mL, AUC = 0.68, p<0.01) was more accurate to identify asymptomatic patients or those who developed symptoms during follow-up. sST2 was independently related to left atrial index (p<0.0001) and aortic valve area (p = 0.004; model R2 = 0.32). A modest correlation was found with BNP (r = 0.4, p<0.01). During follow-up, 29 asymptomatic patients (34%) developed heart failure symptoms. With multivariable analysis, peak aortic jet velocity (HR = 2.7, p = 0.007) and sST2 level (HR = 1.04, p = 0.03) were independent predictors of cardiovascular events. In AS, sST2 levels could provide complementary information regarding symptomatic status, new onset heart failure symptoms and outcome. It might become a promising biomarker in these patients. [less ▲]

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See detailBiological Effects of Cardiac Magnetic Resonance on Human Blood Cells.
LANCELLOTTI, Patrizio ULiege; NCHIMI LONGANG, Alain ULiege; Delierneux, Céline ULiege et al

in Circulation. Cardiovascular imaging (2015), 8(9),

BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used for the diagnosis and management of cardiac diseases. Recent studies have reported immediate post-CMR DNA double-strand breaks in T ... [more ▼]

BACKGROUND: Cardiac magnetic resonance (CMR) is increasingly used for the diagnosis and management of cardiac diseases. Recent studies have reported immediate post-CMR DNA double-strand breaks in T lymphocytes. We sought to evaluate CMR-induced DNA damage in lymphocytes, alterations of blood cells, and their temporal persistence. METHODS AND RESULTS: In 20 prospectively enrolled healthy men (31.4+/-7.9 years), blood was drawn before and after (1-2 hours, 2 days, 1 month, and 1 year) unenhanced 1.5T CMR. Blood cell counts, cell death, and activation status of lymphocytes, monocytes, neutrophils, and platelets were evaluated. The first 2-hour post-CMR were characterized by a small increase of lymphocyte B and neutrophil counts and a transient drop of total lymphocytes because of a decrease in natural killer cells. Among blood cells, only neutrophils and monocytes displayed slight and transient activation. DNA double-strand breaks in lymphocytes were quantified through flow cytometric analysis of H2AX phosphorylation (gamma-H2AX). gamma-H2AX intensity in T lymphocytes did not change early after CMR but increased significantly at day 2 </=1 month before returning to baseline levels of 1-year post-CMR. CONCLUSIONS: Unenhanced CMR is associated with minor but significant immediate blood cell alterations or activations figuring inflammatory response, as well as DNA damage in T lymphocytes observed from day 2 until the first month but disappearing at 1-year follow-up. Although further studies are required to definitely state whether CMR can be used safely, our findings already call for caution when it comes to repeat this examination within a month. [less ▲]

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See detailIn vitro study of the specific interaction between poly (2-dimethylamino ethylmethacrylate) based polymers with platelets and red blood cells.
Flebus, Luca ULiege; Lombart, François ULiege; Martinez-Jothar, L et al

in International Journal of Pharmaceutics (2015), 492

Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous ... [more ▼]

Poly(2-dimethylamino)ethyl methacrylate (PDMAEMA) is an attractive polycation frequently proposed as a non-viral vector for gene therapy. As expected for other cationic carriers, intravenous administration of PDMAEMA can result in its ionic complexation with various negatively charged domains found within the blood. To gain more insight into this polycation hemoreactivity, we followed the binding kinetics of a free form (FF) of fluorescein labelled PDMAEMA (below 15 kDa) in normal human blood using flow cytometry. This in vitro study highlighted that platelets display higher affinity for this polycation compared to red blood cells (RBCs), with an adsorption isotherm characteristics of a specific saturable binding site. PDMAEMA (1-20μg/mL) exerted a concentration dependent proaggregant effect with a biphasic aggregation of washed platelets. Activation of platelets was also noticed in whole blood with the expression of P-selectin and fibrinogen on platelet surface. Although additional studies would be needed in order to elucidate the mechanism of PDMAEMA mediated activation of platelets, our manuscript provides important information on the hemoreactivity of FF PDMAEMA. [less ▲]

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See detailErratum: Elevated basal levels of circulating activated platelets predict ICU-acquired sepsis and mortality: a prospective study.
Layios, N.; Delierneux, Céline ULiege; Hego, A. et al

in Critical care (London, England) (2015), 19(1), 301

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See detailErratum: Prospective immune profiling in critically ill adults: before, during and after severe sepsis and septic shock.
Layios, N.; GOSSET, Christian ULiege; Delierneux, Céline ULiege et al

in Critical care (London, England) (2015), 19(1), 300

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