Christelle Lecut
University of Liège
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Publication
Featured researches published by Christelle Lecut.
Journal of Immunology | 2009
Christelle Lecut; Kim Frederix; Daniel M. Johnson; Christophe Deroanne; Marc Thiry; Céline Faccinetto; Richard J. Evans; Paul G.A. Volders; Vincent Bours; Cécile Oury
ATP, released at the leading edge of migrating neutrophils, amplifies chemotactic signals. The aim of our study was to investigate whether neutrophils express ATP-gated P2X1 ion channels and whether these channels could play a role in chemotaxis. Whole-cell patch clamp experiments showed rapidly desensitizing currents in both human and mouse neutrophils stimulated with P2X1 agonists, αβ-methylene ATP (αβMeATP) and βγMeATP. These currents were strongly impaired or absent in neutrophils from P2X1−/− mice. In Boyden chamber assays, αβMeATP provoked chemokinesis and enhanced formylated peptide- and IL-8-induced chemotaxis of human neutrophils. This agonist similarly increased W-peptide-induced chemotaxis of wild-type mouse neutrophils, whereas it had no effect on P2X1−/− neutrophils. In human as in mouse neutrophils, αβMeATP selectively activated the small RhoGTPase RhoA that caused reversible myosin L chain phosphorylation. Moreover, the αβMeATP-elicited neutrophil movements were prevented by the two Rho kinase inhibitors, Y27632 and H1152. In a gradient of W-peptide, P2X1−/− neutrophils migrated with reduced speed and displayed impaired trailing edge retraction. Finally, neutrophil recruitment in mouse peritoneum upon Escherichia coli injection was enhanced in wild-type mice treated with αβMeATP, whereas it was significantly impaired in the P2X1−/− mice. Thus, activation of P2X1 ion channels by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear. These ion channels may therefore play a significant role in host defense and inflammation.
Blood | 2014
Roxane Darbousset; Céline Delierneux; Soraya Mezouar; Alexandre Hego; Christelle Lecut; Isabelle Guillaumat; Markus A. Riederer; Richard J. Evans; Françoise Dignat-George; Laurence Panicot-Dubois; Cécile Oury; Christophe Dubois
Adenosine triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophil (PMN) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type (WT) mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449, a P2X1 antagonist. Infusion of WT PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from WT mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that adenosine triphosphate (ATP) contributes to polymorphonuclear neutrophil (PMN) activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin, and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanisms by which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs.
Critical Care Medicine | 2013
Diego Castanares-Zapatero; Claire Bouleti; Caroline Sommereyns; Bernhard Gerber; Christelle Lecut; Thomas Mathivet; Michael Horckmans; Didier Communi; Marc Foretz; Jean-Louis Vanoverschelde; Stéphane Germain; Luc Bertrand; Pierre-François Laterre; Cécile Oury; Benoit Viollet; Sandrine Horman; Christophe Beauloye
Objective:As adenosine monophosphate (AMP)-activated protein kinase both controls cytoskeleton organization in endothelial cells and exerts anti-inflammatory effects, we here postulated that it could influence vascular permeability and inflammation, thereby counteracting cardiac wall edema during sepsis. Design:Controlled animal study. Settings:University research laboratory. Subjects:C57BL/6J, &agr;1AMPK–/–, and &agr;1AMPK+/+ mice. Intervention:Sepsis was triggered in vivo using a sublethal injection of lipopolysaccharide (O55B5, 10 mg/kg), inducing systolic left ventricular dysfunction. Left ventricular function, edema, vascular permeability, and inflammation were assessed in vivo in both wild-type mice (&agr;1AMPK+/+) and &agr;1AMP-activated protein kinase–deficient mice (&agr;1AMPK–/–). The 5-aminoimidazole-4-carboxamide riboside served to study the impact of AMP-activated protein kinase activation on vascular permeability in vivo. The integrity of endothelial cell monolayers was also examined in vitro after lipopolysaccharide challenge in the presence of aminoimidazole-4-carboxamide riboside and/or after &agr;1AMP-activated protein kinase silencing. Measurements and Main Results:&agr;1AMP-activated protein kinase deficiency dramatically impaired tolerance to lipopolysaccharide challenge. Indeed, &agr;1AMPK–/– exhibited heightened cardiac vascular permeability after lipopolysaccharide challenge compared with &agr;1AMPK+/+. Consequently, an increase in left ventricular mass corresponding to exaggerated wall edema occurred in &agr;1AMPK–/–, without any further decrease in systolic function. Mechanistically, the lipopolysaccharide-induced &agr;1AMPK–/– cardiac phenotype could not be attributed to major changes in the systemic inflammatory response but was due to an increased disruption of interendothelial tight junctions. Accordingly, AMP-activated protein kinase activation by aminoimidazole-4-carboxamide riboside counteracted lipopolysaccharide-induced hyperpermeability in wild-type mice in vivo as well as in endothelial cells in vitro. This effect was associated with a potent protection of zonula occludens-1 linear border pattern in endothelial cells. Conclusions:Our results demonstrate for the first time the involvement of a signaling pathway in the control of left ventricular wall edema during sepsis. AMP-activated protein kinase exerts a protective action through the preservation of interendothelial tight junctions. Interestingly, exaggerated left ventricular wall edema was not coupled with aggravated systolic dysfunction. However, it could contribute to diastolic dysfunction in patients with sepsis.
Journal of Thrombosis and Haemostasis | 2012
Christelle Lecut; Céline Faccinetto; Céline Delierneux; R. van Oerle; Henri M.H. Spronk; Richard J. Evans; J. El Benna; Vincent Bours; Cécile Oury
Summary. Background: In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP‐gated P2X1 ion channels are involved in promoting neutrophil chemotaxis.
PubMed | 2012
Christelle Lecut; Céline Faccinetto; Céline Delierneux; van Oerle R; Henri M.H. Spronk; Richard J. Evans; El Benna J; Bours; Cécile Oury
Summary. Background: In sepsis, extracellular ATP, secreted by activated platelets and leukocytes, may contribute to the crosstalk between hemostasis and inflammation. Previously, we showed that, in addition to their role in platelet activation, ATP‐gated P2X1 ion channels are involved in promoting neutrophil chemotaxis.
Journal of Thrombosis and Haemostasis | 2014
Marie-Blanche Onselaer; Cécile Oury; Roger W. Hunter; Stéphane Eeckhoudt; N Barile; Christelle Lecut; Nicole Morel; Benoit Viollet; L-M Jacquet; Luc Bertrand; Kei Sakamoto; Jean-Louis Vanoverschelde; Christophe Beauloye; Sandrine Horman
Platelet activation requires sweeping morphologic changes, supported by contraction and remodeling of the platelet actin cytoskeleton. In various other cell types, AMP‐activated protein kinase (AMPK) controls the phosphorylation state of cytoskeletal targets.
Journal of Immunology | 2012
Emilie Theatre; Kim Frederix; William Guilmain; Céline Delierneux; Christelle Lecut; Lucien Bettendorff; Vincent Bours; Cécile Oury
In airways, the ecto-nucleoside triphosphate diphosphohydrolase CD39 plays a central role in the regulation of physiological mucosal nucleotide concentrations and likely contributes to the control of inflammation because accelerated ATP metabolism occurs in chronic inflammatory lung diseases. We sought to determine whether constant elevated CD39 activity in lung epithelia is sufficient to cause inflammation and whether this affects the response to acute LPS or Pseudomonas aeruginosa exposure. We generated transgenic mice overexpressing human CD39 under the control of the airway-specific Clara cell 10-kDa protein gene promoter. Transgenic mice did not develop any spontaneous lung inflammation. However, intratracheal instillation of LPS resulted in accelerated recruitment of neutrophils to the airways of transgenic mice. Macrophage clearance was delayed, and the amounts of CD8+ T and B cells were augmented. Increased levels of keratinocyte chemoattractant, IL-6, and RANTES were produced in transgenic lungs. Similarly, higher numbers of neutrophils and macrophages were found in the lungs of transgenic mice infected with P. aeruginosa, which correlated with improved bacteria clearance. The transgenic phenotype was partially and differentially restored by coinstillation of P2X1 or P2X7 receptor antagonists or of caffeine with LPS. Thus, a chronic increase of epithelial CD39 expression and activity promotes airway inflammation in response to bacterial challenge by enhancing P1 and P2 receptor activation.
Computational and structural biotechnology journal | 2015
Cécile Oury; Christelle Lecut; Alexandre Hego; Odile Wéra; Céline Delierneux
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 this model, 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.
Circulation | 2015
Lucia Musumeci; Marijke J.E. Kuijpers; Karen Gilio; Alexandre Hego; Emilie Théâtre; Lisbeth Maurissen; Maud Vandereyken; Catia V Diogo; Christelle Lecut; William Guilmain; Ekaterina V. Bobkova; Johannes A. Eble; Russell Dahl; Pierre Drion; Justin Rascon; Yalda Mostofi; Hongbin Yuan; Eduard Sergienko; Thomas Dy Chung; Marc Thiry; Yotis A. Senis; Michel Moutschen; Tomas Mustelin; Patrizio Lancellotti; Johan W. M. Heemskerk; Lutz Tautz; Cécile Oury; Souad Rahmouni
Background— A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases 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 by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on 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 phospholipase C&ggr;2 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 C-type lectin-like receptor 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 C-type lectin-like receptor 2–mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug.
Nature Communications | 2018
Yukihide Momozawa; Julia Dmitrieva; Emilie Théâtre; Valérie Deffontaine; Souad Rahmouni; Benoit Charloteaux; François Crins; Elisa Docampo; Mahmoud Elansary; Ann-Stephan Gori; Christelle Lecut; Rob Mariman; Myriam Mni; Cécile Oury; Ilya Altukhov; Dmitry Alexeev; Yuri Aulchenko; Leila Amininejad; Gerd Bouma; Frank Hoentjen; M. Lowenberg; Bas Oldenburg; Marieke Pierik; Andrea E. van der Meulen-de Jong; C. Janneke van der Woude; Marijn C. Visschedijk; Mark Lathrop; Jean-Pierre Hugot; Rinse K. Weersma; Martine De Vos
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.