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2. CD146 at the Interface between Oxidative Stress and the Wnt Signaling Pathway in Systemic Sclerosis

Author

Heim, Xavier, Bermudez, Julien, Joshkon, Ahmad, Kaspi, Elise, Bachelier, Richard, Nollet, Marie, Vélier, Mélanie, Dou, Laetitia, Brodovitch, Alexandre, Foucault-Bertaud, Alexandrine, Leroyer, Aurelie S., Benyamine, Audrey, Daumas, Aurélie, Granel, Brigitte, Sabatier, Florence, Dignat-George, Françoise, Blot-Chabaud, Marcel, and Bardin, Nathalie

Published
2022
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8. Plasmatic Level of Leukocyte-Derived Microparticles Is Associated With Unstable Plaque in Asymptomatic Patients With High-Grade Carotid Stenosis

Author

Sarlon-Bartoli, Gabrielle, Bennis, Youssef, Lacroix, Romaric, Piercecchi-Marti, Marie Dominique, Bartoli, Michel A., Arnaud, Laurent, Mancini, Julien, Boudes, Audrey, Sarlon, Emmanuelle, Thevenin, Benjamin, Leroyer, Aurelie S., Squarcioni, Christian, Magnan, Pierre Edouard, Dignat-George, Françoise, and Sabatier, Florence

Published
2013
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9. Additional file 1 of Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma

Author

Joshkon, Ahmad, Tabouret, Emeline, Traboulsi, Wael, Bachelier, Richard, Simoncini, Stéphanie, Roffino, Sandrine, Jiguet-Jiglaire, Carine, Badran, Bassam, Guillet, Benjamin, Foucault-Bertaud, Alexandrine, Leroyer, Aurelie S., Dignat-George, Françoise, Chinot, Olivier, Fayyad-Kazan, Hussein, Bardin, Nathalie, and Blot-Chabaud, Marcel

Abstract

Additional file 1. Supplementary methods:Peptides and antibodies. Plasmids, siRNA and cell transfection. Western-blot and Immunoprecipitation assays. ELISA experiments. Immunofluorescence experiments. Flow cytometry experiments. Reverse Transcription-quantitative PCR (RT-qPCR). Cell migration assays. Cell Proliferation assays. Transwell invasion assays. Crispr/Cas9 deletion of genes. Experiments on animals and imaging. Immunohistochemistry. Patient cohort. Statistical analysis. Supplementary figures and tables: Supplementary Table 1: Absence of significant impact of age, KPS and steroid dose on progression-free survival or overall survival. Supplementary Table 2: references and application condition of the different antibodies used in the study. Supplementary Figure 1: Expression of CD146 on various types of cancers and effect on overall survival in patients with GBM. Supplementary Figure 2: Glioblastoma cell lines characterization. Supplementary Figure 3: Concentration of VEGF and sCD146 in the culture media of U87, U373, and U118 glioblastoma cell lines. Supplementary Figure 4: Avastin induces proliferation, sCD146 secretion, and EMT/CSC markers in U373 cells. Supplementary Figure 5: Avastin has no effect on CD146-negative U118 glioblastoma cells. Supplementary Figure 6: sCD146 induces U373 cell proliferation, migration and invasion in-vitro and promotes CSC and EMT markers. Supplementary Figure 7: Effect of sCD146 and VEGF on CD146-negative glioblastoma cells. Supplementary Figure 8: sCD146 binds integrin αvβ3 on U373 cells. Supplementary Figure 9: Soluble CD146 induces EMT in U118 cells transfected with integrin αvβ3. Supplementary Figure 10: Knocking-down integrin αvβ3 inhibits sCD146-induced EMT in U87 cells. Supplementary Figure 11: sCD146 mediated its effects on U87 cells through a signalosome containing CD146, αvβ3, and VEGFR2. Supplementary Figure 12: sCD146 mediates its effects on U373 cells through a signalosome containing CD146, αvβ3, and VEGFR2. Supplementary Figure 13: Validating gene knock out in U87 and U373 cells. Supplementary Figure 14: Integrin αvβ3 associates with membrane CD146 and VEGFR2 on HUVECs and binds sCD146. Supplementary Figure 15: CD146/VEGFR2/integrin αvβ3 signalosome mediates sCD146 and VEGF effects in U87 cells and activates common signaling pathways. Supplementary Figure 16: CD146/VEGFR2/integrin αvβ3 signalosome mediates sCD146 and VEGF effects in U373 cells and activates common signaling pathways. Supplementary Figure 17: CD146, integrin αvβ3, and VEGFR2 are essential for mediating sCD146 and VEGF effects on U87 cells. Supplementary Figure 18: CD146, integrin αvβ3, and VEGFR2 are essential for mediating sCD146 and VEGF effects on U373 cells. Supplementary Figure 19: Humanized anti-sCD146 antibody mucizumab significantly decreases U373 cell proliferation, migration and invasion and hampers CSC and EMT in-vitro. Supplementary Figure 20: Humanized anti-sCD146 mucizumab significantly decreases human sCD146 and human VEGF in two different mouse models of glioblastoma. Supplementary Figure 21: Illustrative summary describing the mechanism of resistance to bevacizumab in CD146-positive glioblastoma cells.

Published
2022
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10. Positional transcriptomics shed light on site-specific pathologies of the aorta

Author

Romay, Milagros, primary, Ma, Feiyang, additional, Hernandez, Gloria, additional, Vandestienne, Marie, additional, Kimball, Todd, additional, Silvestro, Michele, additional, Hadi, Tarik, additional, Reyes, Andrew, additional, Ramirez, Margaret, additional, Bardin, Nathalie, additional, Blot-Chabaud, Marcel, additional, Pellegrini, Matteo, additional, Leroyer, Aurelie, additional, Ait-Oufella, Hafid, additional, Ramkhelawon, Bhama, additional, and Iruela-Arispe, M. Luisa, additional

Published
2021
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13. Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis—Contribution of New Antibodies for Therapy

Author

Joshkon, Ahmad, primary, Heim, Xavier, additional, Dubrou, Cléa, additional, Bachelier, Richard, additional, Traboulsi, Wael, additional, Stalin, Jimmy, additional, Fayyad-Kazan, Hussein, additional, Badran, Bassam, additional, Foucault-Bertaud, Alexandrine, additional, Leroyer, Aurelie S., additional, Bardin, Nathalie, additional, and Blot-Chabaud, Marcel, additional

Published
2020
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14. Increased vitreous shedding of microparticles in proliferative diabetic retinopathy stimulates endothelial proliferation

Author

Chahed, Sadri, Leroyer, Aurelie S., Benzerroug, Mounir, Gaucher, David, Georgescu, Adriana, Picaud, Serge, Silvestre, Jean-Sebastien, Gaudric, Alain, Tedgui, Alain, Massin, Pascale, and Boulanger, Chantal M.

Subjects
Diabetic retinopathy -- Development and progression -- Complications and side effects -- Research, Epithelial cells -- Physiological aspects -- Research, Health
Abstract

OBJECTIVE--Diabetic retinopathy is associated with progressive retinal capillary activation and proliferation, leading to vision impairment and blindness. Microparticles are submicron membrane vesicles with biological activities, released following cell activation or apoptosis. We tested the hypothesis that proangiogenic microparticles accumulate in vitreous fluid in diabetic retinopathy. RESEARCH DESIGN AND METHODS--Levels and cellular origin of Vitreous and plasma microparticles from control (n = 26) and diabetic (n = 104) patients were analyzed by flow cytometry, and their proangiogenic activity was assessed by in vitro thymidine incorporation and neovessel formation in subcutaneous Matrigel plugs in mice. RESULTS--Microparticles of endothelial, platelet, photoreceptor, and microglial origin were identified in vitreous samples. Levels of photoreceptor and microglial microparticles were undetectable in plasmas but were comparable in diabetic and control vitreous samples. Vitreous platelet and endothelial microparticles levels were increased in diabetic patients and decreased following panretinal laser photocoagulation or intravitreal antivascular endothelial growth factor injection in proliferative diabetic retinopathy (PDR). The ratio of Vitreous to plasma microparticle levels was calculated to estimate local formation versus potential plasma leakage. In PDR, the endothelial mieroparticles ratio--but not that for platelet--was greater than 1.0, indicating local formation of endothelial microparticles from retinal vessels and permeation of platelet microparticles from plasma. Isolated Vitreous microparticles stimulated by 1.6-fold endothelial proliferation and increased new vessel formation in mice. CONCLUSIONS--The present study demonstrates that vitreous fluid contains shed membrane microparticles of endothelial, platelet, and retinal origin. Vitreous microparticles levels are increased in patients with diabetic retinopathy, where they could contribute to disease progression. Diabetes 59:694-701, 2010, Despite advances in medical care, diabetic retinopathy continues to be a leading cause of vision impairment and blindness in working-age adults (1). The pathogenesis of diabetic retinopathy is complex and [...]

Published
2010
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16. Randomized controlled trial protocol to investigate the antiplatelet therapy effect on extracellular vesicles (AFFECT EV) in acute myocardial infarction

Author

Gasecka, Alecja, Nieuwland, R, Budnik, Mateusz, Dignat-George, Francoise, EYILETEN, c, Harrison, Peter, HUCZEK, Z, KAPLON-CIESLICKA, A, Lacroix, Romaric, Opolski, Grzegorz, Pluta, Kacper, VAN DER POL, E, POSTULA, M, Leroyer, Aurelie S, SILJANDER, P, STURK, A, FILIPIAK, KJ, Medical University of Warsaw - Poland, University of Amsterdam [Amsterdam] (UvA), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Birmingham [Birmingham], and University of Helsinki

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

17. The Critical Role of Interleukin-33 in Promoting Angiogenesis and Regulates Inflammation through Mast Cells in Takayasu Arteritis

Author

Desbois, Anne-Claire, Cacoub, Patrice, Leroyer, Aurelie, Tellier, Edwige, Garrido, Marlene, Maciejewski-Duval, Anna, Comarmond, Cloe, Barete, Stephane, Arock, Michel, Bruneval, Patrick, Launay, Jean-Marie, Fouret, Pierre, Blank, Ulrich, Michelle Rosenzwajg, Klatzman, David, Jarraya, Mohamed, Cluzel, Philippe, Koskas, Fabien, Kaplanski, Gilles, Saadoun, David, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2017

18. CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation

Author

Leroyer, Aurelie, Jouve, Nathalie, Bachelier, Richard, Despoix, Nicolas, Blin, Muriel, Matinzadeh, Maryam Khalili, Poitevin, Stéphane, Aurrand-Lions, Michel, Fallague, Karim, Bardin, Nathalie, Blot-Chabaud, Marcel, Vely, Frédéric, Dignat-George, Françoise, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2015

20. The neurotrophin receptor p75NTR triggers endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impairment of reparative neovascularization

Author

Caporali, Andrea, Pani, Elisabetta, Horrevoets, Anton J. G., Kraenkel, Nicolle, Oikawa, Atsuhiko, Sala-Newby, Graciela B., Meloni, Marco, Cristofaro, Brunella, Graiani, Gallia, Leroyer, Aurelie, Boulanger, Chantal, Herman, Andrew, Spinetti, Gaia, Yoon, Sung Ok, Madeddu, Paolo, and Emanueli, Costanza

Subjects
Male, Vascular Endothelial Growth Factor A, Neovascularization, Physiologic, Apoptosis, Mice, Inbred Strains, Nitric Oxide, Transfection, Receptor, Nerve Growth Factor, Article, Streptozocin, Diabetes Mellitus, Experimental, Disease Models, Animal, Mice, Ischemia, Animals, Humans, sense organs, Endothelium, Vascular, Nitric Oxide Synthase, Muscle, Skeletal, Proto-Oncogene Proteins c-akt, Cells, Cultured, Diabetic Angiopathies, Signal Transduction
Abstract

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75(NTR)), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75(NTR) expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75(NTR) gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75(NTR) depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75(NTR). Collectively, our data newly demonstrate the antiangiogenic action of p75(NTR) and open new avenues for the therapeutic use of p75(NTR) inhibition to combat diabetes-induced microvascular liabilities.

Published
2008

21. Microparticles and sudden cardiac death due to coronary occlusion. The TIDE (Thrombus and Inflammation in sudden DEath) study

Author

Empana, Jean-Philippe, primary, Boulanger, Chantal M, additional, Tafflet, Muriel, additional, Renard, Jean M, additional, Leroyer, Aurelie S, additional, Varenne, Olivier, additional, Prugger, Christof, additional, Silvain, Johanne, additional, Tedgui, Alain, additional, Cariou, Alain, additional, Montalescot, Gilles, additional, Jouven, Xavier, additional, and Spaulding, Christian, additional

Published
2014
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22. Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

Author

Cristofaro, Brunella, primary, Shi, Yu, additional, Faria, Marcella, additional, Suchting, Steven, additional, Leroyer, Aurelie S., additional, Trindade, Alexandre, additional, Duarte, Antonio, additional, Zovein, Ann C., additional, Iruela-Arispe, M. Luisa, additional, Nih, Lina R., additional, Kubis, Nathalie, additional, Henrion, Daniel, additional, Loufrani, Laurent, additional, Todiras, Mihail, additional, Schleifenbaum, Johanna, additional, Gollasch, Maik, additional, Zhuang, Zhen W., additional, Simons, Michael, additional, Eichmann, Anne, additional, and le Noble, Ferdinand, additional

Published
2013
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23. C0082 Circulating leukocyte- and endothelial-derived microparticles support a fibrinolytic activity

Author

Lacroix, Romaric, primary, Plawinski, Laurent, additional, Robert, Stéphane, additional, Doeuvre, Loïc, additional, Sabatier, Florence, additional, de Lizarrondo, Sara Martinez, additional, Mezzapesa, Anna, additional, Anfosso, Francine, additional, Leroyer, Aurelie S., additional, Poullin, Pascale, additional, Jourde, Noémie, additional, Njock, Sébastien M., additional, Vivien, Denis, additional, Boulanger, Chantal M., additional, Angles-Cano, Eduardo, additional, and Dignat-George, Françoise, additional

Published
2012
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24. Proteomics, Metabolomics, and Immunomics on Microparticles Derived From Human Atherosclerotic Plaques

Author

Mayr, Manuel, primary, Grainger, David, additional, Mayr, Ursula, additional, Leroyer, Aurelie S., additional, Leseche, Guy, additional, Sidibe, Anissa, additional, Herbin, Olivier, additional, Yin, Xiaoke, additional, Gomes, Aldrin, additional, Madhu, Bassetti, additional, Griffiths, John R., additional, Xu, Qingbo, additional, Tedgui, Alain, additional, and Boulanger, Chantal M., additional

Published
2009
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25. Microparticles From Ischemic Muscle Promotes Postnatal Vasculogenesis

Author

Leroyer, Aurelie S., primary, Ebrahimian, Téni G., additional, Cochain, Clément, additional, Récalde, Alice, additional, Blanc-Brude, Olivier, additional, Mees, Barend, additional, Vilar, José, additional, Tedgui, Alain, additional, Levy, Bernard I., additional, Chimini, Giovanna, additional, Boulanger, Chantal M., additional, and Silvestre, Jean-Sébastien, additional

Published
2009
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26. Neurotrophin p75 Receptor (p75 NTR ) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis

Author

Caporali, Andrea, primary, Pani, Elisabetta, additional, Horrevoets, Anton J.G., additional, Kraenkel, Nicolle, additional, Oikawa, Atsuhiko, additional, Sala-Newby, Graciela B., additional, Meloni, Marco, additional, Cristofaro, Brunella, additional, Graiani, Gallia, additional, Leroyer, Aurelie S., additional, Boulanger, Chantal M., additional, Spinetti, Gaia, additional, Yoon, Sung Ok, additional, Madeddu, Paolo, additional, and Emanueli, Costanza, additional

Published
2008
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28. Microparticles and sudden cardiac death due to coronary occlusion. The TIDE (Thrombus and Inflammation in sudden DEath) study

Author

Empana, Jean-Philippe, Boulanger, Chantal M, Tafflet, Muriel, Renard, Jean M, Leroyer, Aurelie S, Varenne, Olivier, Prugger, Christof, Silvain, Johanne, Tedgui, Alain, Cariou, Alain, Montalescot, Gilles, Jouven, Xavier, and Spaulding, Christian

Abstract

Aims: The pattern of coronary occlusion might contribute to the onset of ventricular arrhythmia and sudden cardiac death (SCD). We hypothesized that the concentrations of microparticles might differ between SCD and ST-elevation myocardial infarction (STEMI) patients without rhythmic disturbances.Methods and results: The study sample includes consecutive patients hospitalized in two French tertiary centres between 2006 and 2011 for SCD with angiographically-proven acute coronary occlusion (n=23), for STEMI (n=61) and for a planned percutaneous coronary angioplasty (PCI) (n=35, controls). During PCI blood was collected in the arch of aorta (systemic blood) before and after the procedure and in the culprit coronary lesion with an aspiration catheter. Microparticles were analysed by flow cytometry in a blinded manner to quantify endothelial (CD144+), platelet (CD41+), leucocyte (CD11a+) and erythrocyte (CD235a+) derived microparticles. After multivariate analysis, intracoronary concentrations of endothelial-derived microparticles were significantly higher in SCD than in STEMI patients (129 (74–185) vs. 50 (21–118) nb/µl; p< 0.01). Intracoronary and systemic blood concentrations of platelet-derived microparticles were not different between SCD and controls, suggesting limited impact of cardiac massage and electric defibrillation in microparticle concentrations.Conclusion: The higher concentrations of endothelial-derived microparticles in SCD due to acute coronary occlusion compared with STEMI without rhythmic disturbances suggests different patterns of acute coronary occlusion.

Published
2015
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32. The Role of the Adhesion Receptor CD146 and Its Soluble Form in Human Embryo Implantation and Pregnancy

Author

Sylvie Bouvier, Elise Kaspi, Ahmad Joshkon, Odile Paulmyer-Lacroix, Marie-Dominique Piercecchi-Marti, Akshita Sharma, Aurélie S. Leroyer, Alexandrine Bertaud, Jean-Christophe Gris, Françoise Dignat-George, Marcel Blot-Chabaud, Nathalie Bardin, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), D.Y. Patil University , Kolhapur, India, Sechenov First Moscow State Medical University, Leroyer, Aurelie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and I.M. Sechenov First Moscow State Medical University [Moscow, Russia] (MSMU)

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Angiogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Mini Review, Immunology, CD146 Antigen, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Biology, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, In vivo, Pregnancy, medicine, Immunology and Allergy, Humans, Embryo Implantation, Receptor, 030304 developmental biology, 0303 health sciences, In vitro fertilisation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Embryo, Biomarker, RC581-607, medicine.disease, Implantation, Cell biology, Fertility, CD146/sCD146, 030220 oncology & carcinogenesis, embryonic structures, CD146, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Immunologic diseases. Allergy, Biomarkers
Abstract

CD146 is an adhesion molecule essentially located in the vascular system, which has been described to play an important role in angiogenesis. A soluble form of CD146, called sCD146, is detected in the bloodstream and is known as an angiogenic factor. During placental development, CD146 is selectively expressed in extravillous trophoblasts. A growing body of evidence shows that CD146 and, in particular, sCD146, regulate extravillous trophoblasts migration and invasion both in vitro and in vivo. Hereby, we review expression and functions of CD146/sCD146 in the obstetrical field, mainly in pregnancy and in embryo implantation. We emphasized the relevance of quantifying sCD146 in the plasma of pregnant women or in embryo supernatant in the case of in vitro fertilization (IVF) to predict pathological pregnancy such as preeclampsia or implantation defect. This review will also shed light on some major results that led us to define CD146/sCD146 as a biomarker of placental development and paves the way toward identification of new therapeutic targets during implantation and pregnancy.

Published
2021

33. Extracellular vesicles from T cells overexpress miR-146b-5p in HIV-1 infection and repress endothelial activation

Author

Corinne Chareyre, Stéphane Robert, Stéphanie Simoncini, Françoise Dignat-George, Aurélie S. Leroyer, Patrice Roll, Olivia Zaegel-Faucher, Luc Lyonnet, Joëlle Micallef, Romaric Lacroix, Estelle Balducci, Isabelle Poizot-Martin, Dilyana Todorova, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Leroyer, Aurelie, French National Agency for Research on AIDS and Viral Hepatitis, Bartoli, Marc, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)

Subjects
0301 basic medicine, Adult, CD4-Positive T-Lymphocytes, Male, Cell biology, RNase P, T cell, [SDV]Life Sciences [q-bio], lcsh:Medicine, HIV Infections, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Cell Line, Endothelial activation, 03 medical and health sciences, Extracellular Vesicles, 0302 clinical medicine, Downregulation and upregulation, In vivo, microRNA, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, lcsh:Science, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, lcsh:R, Endothelial Cells, In vitro, 3. Good health, Up-Regulation, [SDV] Life Sciences [q-bio], MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Case-Control Studies, HIV-1, Female, lcsh:Q, 030217 neurology & neurosurgery, Homeostasis, Cell signalling
Abstract

Human immunodeficiency virus type 1 (HIV-1) infection promotes a generalized activation of host responses that involves not only CD4 T cells, but also cells of the microenvironment, which are not directly infected, such as endothelial cells. The mechanisms triggering HIV-1-associated vascular alterations remain poorly understood. Extracellular vesicles (EVs), implicated in cell-to-cell communication, have been recently described as carriers of microRNAs (miRNAs). Here, we show that miR-146b-5p is upregulated in both CD4 T cells, CD4 T cell-derived EVs and circulating EVs obtained from antiretroviral therapy-naive HIV-1-infected patients. We further demonstrate that EVs from T cell line overexpressing miR-146b-5p mimics (miR-146b-EVs): 1) protect their miRNA cargo from RNase degradation, 2) transfer miR-146b-5p mimics into endothelial cells and 3) reduce endothelial inflammatory responses in vitro and in vivo in the lungs of mice through the downregulation of nuclear factor-κB-responsive molecules. These data advance our understanding on chronic inflammatory responses affecting endothelial homeostasis, in infectious and non-infectious diseases and pave the way for potential new anti-inflammatory strategies.

Published
2019

34. Endothelial-Specific Deletion of CD146 Protects Against Experimental Glomerulonephritis in Mice

Author

Alexandrine Foucault-Bertaud, Richard Bachelier, Panagiotis Kavvadas, Maja T. Lindenmeyer, Ahmad Joshkon, Nathalie Bardin, Ahmed Abed, Noémie Jourde-Chiche, Clemens D. Cohen, Christos E. Chadjichristos, Florence Authier, Françoise Dignat-George, Stéphane Burtey, Magali Genest, Aurélie S. Leroyer, Marcel Blot-Chabaud, Common and Rare Kidney Diseases = Maladies Rénales Fréquentes et Rares: des Mécanismes Moléculaires à la Médecine Personnalisée (CORAKID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Contextes, Variation, Usages : Groupe de Recherche en linguistique des langues germaniques et scandinaves de Paris-Sorbonne (CoVariUs), Université Paris-Sorbonne (UP4), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-11-BSV1-0019,READ,CD146 et JAMs dans le contrôle de l'intégrité des junctions endothéliales : des bases moléculaires aux maladies inflammatoires rénales.(2011), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Ludwig-Maximilians University [Munich] (LMU), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Chadjichristos, Christos, Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée (CoRaKID), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ludwig Maximilian University [Munich] (LMU), and Leroyer, Aurelie

Subjects
0301 basic medicine, mice, [SDV]Life Sciences [q-bio], Kidney Glomerulus, Inflammation, CD146 Antigen, 030204 cardiovascular system & hematology, urologic and male genital diseases, Experimental glomerulonephritis, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gene Knockout Techniques, 03 medical and health sciences, Glomerulonephritis, 0302 clinical medicine, Fibrosis, Drug Discovery, Internal Medicine, Animals, Medicine, Proteinuria, business.industry, Monocyte, fibrosis, Endothelial Cells, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Up-Regulation, [SDV] Life Sciences [q-bio], Disease Models, Animal, Intercellular Junctions, 030104 developmental biology, medicine.anatomical_structure, inflammation, Immunology, monocyte, CD146, medicine.symptom, proteinuria, business
Abstract

International audience; CD146 is an endothelial junctional adhesion molecule, which expression is increased in human glomerular diseases. However, the pathological significance of this overexpression remains unknown. Induction of glomerulonephritis in mice, by using nephrotoxic serum, showed that CD146 expression was highly induced within damaged glomeruli and was associated with renal inflammation and fibrosis. Interestingly, 2 weeks after glomerulonephritis induction, CD146 knockout mice showed preserved renal function as proteinuria and blood urea nitrogen levels were significantly lower compared with wild-type littermates. Furthermore, renal structure was considerably conserved, since crescents formation, tubular dilation, monocyte and lymphocyte infiltration, and interstitial renal fibrosis were highly reduced. Colocalization with markers for different types of glomerular cells showed that CD146 expression was mainly increased within the injured endothelium of the glomerular tuft. Consequently, we generated a new transgenic strain in which CD146 was specifically deleted in the vascular endothelium. Similarly to CD146 knockout, these mice showed preservation of renal structure and function after the induction of glomerulonephritis compared with wild-type animals. These data show that endothelial CD146 plays a major role in glomerulonephritis and may represent a novel therapeutic target to reduce glomerular damage and the progression of renal disease.

Published
2021

35. Multifaceted role of extracellular vesicles in atherosclerosis

Author

Florence Sabatier, Anne-Claire Duchez, Cléa Dubrou, Aurélie S. Leroyer, Akhil Konkoth, Françoise Dignat-George, Romaric Lacroix, Ronald Saraswat, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Assistance Publique - Hôpitaux de Marseille (APHM), European Project: 9813409(1998), Lucas, Nelly, Pattern Formation in Nonlinear, Nonequilibrium Systems - 1998-11-01 - 2002-10-31 - 9813409 - VALID, and Leroyer, Aurelie

Subjects
0301 basic medicine, Senescence, Extracellular vesicles Atherosclerosis Biomarkers Hemostasis Senescence, Angiogenesis, Bioactive molecules, [SDV]Life Sciences [q-bio], Inflammation, Cell Communication, 030204 cardiovascular system & hematology, Exosomes, Extracellular vesicles, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell-Derived Microparticles, Medicine, Humans, A determinant, Hemostasis, business.industry, Atherosclerosis, Microvesicles, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Cell activation, Neuroscience, Biomarkers
Abstract

International audience; Extracellular vesicles (EVs) are small vesicles released by the majority of cells in response to cell activation or death stimuli. They are grouped as small EVs or exosomes, large EVs such as microvesicles (MVs) and apoptotic bodies, resulting from distinct mechanisms of generation. EVs are released into the extracellular space, in most human biological fluids and tissues, including atherosclerotic plaques. They transport complex cargo of bioactive molecules, including proteins, lipids and genetic material and are therefore involved in pathophysiological pathways of cell-cell communication. Indeed, EVs are involved in several processes such as inflammation, coagulation, vascular dysfunction, angiogenesis and senescence, contributing to the initiation and progression of atherothrombotic diseases. Consequently, they behave as a determinant of atherosclerotic plaque vulnerability leading to major cardiovascular disorders. Over the last decade, the field of EVs research has grown, highlighting their involvement in atherosclerosis. However, limitations in both detection methodologies and standardisation have hindered implementation of EVs in the clinical settings. This review summarizes the effect of EVs in atherosclerosis development, progression and severity, with specific attention devoted to their ambivalent roles in senescence and hemostasis. This review will also highlight the role of MVs as multifaceted messengers, able to promote or to attenuate atherosclerosis progression. Finally, we will discuss the main technical challenges and prerequisites of standardization for driving EVs to the clinics and delineate their relevance as emergent biomarkers and innovative therapeutic approaches in atherosclerosis.

Published
2021

36. CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases

Author

Heim, Xavier, Joshkon, Ahmad, Bermudez, Julien, Bachelier, Richard, Dubrou, Cléa, Boucraut, José, Foucault-Bertaud, Alexandrine, Leroyer, Aurélie, Dignat-George, Francoise, Blot-Chabaud, Marcel, Bardin, Nathalie, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Nord [CHU - APHM], Institut de Neurosciences de la Timone (INT), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lucas, Nelly, and Leroyer, Aurelie

Subjects
[SDV] Life Sciences [q-bio], soluble CD146, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, lcsh:Biology (General), CD146, inflammation angiogenesis, [SDV]Life Sciences [q-bio], autoimmunity, Review, lcsh:QH301-705.5, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.

Published
2020

37. Sera From Patients With Minimal Change Disease Increase Endothelial Permeability to Sodium

Author

Manon Carre, Richard Bachelier, Nathalie Bardin, Karim Fallague, Françoise Dignat-George, Florence Daviet, Manon Laforêt, Stéphane Burtey, Marcel Blot-Chabaud, Stéphane Poitevin, Noémie Jourde-Chiche, Muriel G. Blin, Aurélie S. Leroyer, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Leroyer, Aurelie, Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Prémilleux, Annick

Subjects
Endothelial permeability, Sodium, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, chemistry.chemical_element, 030204 cardiovascular system & hematology, Pharmacology, lcsh:RC870-923, Alimentation, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, 0302 clinical medicine, Research Letter, Medicine, Minimal change disease, Marseille, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Agriculture, lcsh:Diseases of the genitourinary system. Urology, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, [SDV] Life Sciences [q-bio], chemistry, Nephrology, France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; E dema is the main symptom of nephrotic syndrome associated to minimal change disease (MCD). Besides the increase in glomerular permeability, possibly induced by a circulating permeability factor, 1 an increase in systemic vascular permeability could participate in the constitution of edema. This study was conducted to evaluate the permeability of endothelial cells (EC) exposed to serum from nephrotic patients with MCD, to low-or high-molecularweight molecules, by trans-or paracellular transport.

Published
2020

38. Immunomodulatory role of Interleukin-33 in large vessel vasculitis

Author

Aurélie S. Leroyer, Jean-Marie Launay, Marlène Garrido, Gilles Kaplanski, A.C. Desbois, Philippe Cluzel, Michel Arock, Anna Maciejewski-Duval, Cloé Comarmond, Stéphane Barete, Michelle Rosenzwajg, David Klatzmann, Ulrich Blank, Fabien Koskas, Patrice Cacoub, Edwige Tellier, Pierre Fouret, David Saadoun, Patrick Bruneval, Mohamed Jarraya, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Service de Chirurgie cardiaque et thoracique [CHU Pitié-Salpêtrière], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Gestionnaire, Hal Sorbonne Université, Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), École normale supérieure - Cachan (ENS Cachan), Faculte de Medecine Xavier Bichat, Université Paris Diderot - Paris 7 (UPD7), Leroyer, Aurelie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], DIGNAT-GEORGE, Françoise, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP]

Subjects
Male, 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Giant Cell Arteritis, lcsh:Medicine, Inflammation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Flow cytometry, 03 medical and health sciences, Th2 Cells, 0302 clinical medicine, Large vessel vasculitis, medicine, Humans, Mast Cells, lcsh:Science, Receptor, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, 030203 arthritis & rheumatology, Multidisciplinary, medicine.diagnostic_test, business.industry, Interleukins, lcsh:R, Interleukin-33, Acquired immune system, medicine.disease, Interleukin-1 Receptor-Like 1 Protein, 3. Good health, Interleukin 33, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunology, lcsh:Q, Female, medicine.symptom, business, Vasculitis, Cell signalling
Abstract

The mechanisms regulating inflammation in large vessels vasculitis (LVV) are poorly understood. Interleukin 33 (IL-33) has been shown to license innate and adaptive immunity by enhancing Th2 cytokines production. We aimed to examine the role of IL-33 in the immunomodulation of T cell activation in LVV. T cell homeostasis and cytokines production were determined in peripheral blood from 52 patients with giant cell arteritis (GCA) and 50 healthy donors (HD), using Luminex assay, flow cytometry, quantitative RT-PCR and by immunofluorescence analysis in inflammatory aorta lesions. We found increased level of IL-33 and its receptor ST2/IL-1R4 in the serum of patient with LVV. Endothelial cells were the main source of IL-33, whereas Th2 cells, Tregs and mast cells (MC) express ST2 in LVV vessels. IL-33 had a direct immunomodulatory impact by increasing Th2 and Tregs. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs (p = 0.008). Stimulation of MC by IL-33 increased indoleamine 2 3-dioxygenase (IDO) activity and IL-2 secretion. IL-33 mRNA expression was significantly correlated with the expression of IL-10 and TGF-β within aorta inflammatory lesions. To conclude, our findings suggest that IL-33 may exert a critical immunoregulatory role in promoting Tregs and Th2 cells in LVV.

Published
2020

39. TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis

Author

Alexandrine Bertaud, Monia Khanfir, Raja Marrakchi, Houman Mh, Aurélie S. Leroyer, Brigitte Granel, Xavier Heim, Marcel Blot-Chabaud, Bilel Neili, Ahmed Abidi, Amira Gabsi, F. Said, Asma Gati, Nathalie Bardin, Haifa Sakhri, Sonia Amri, Akram Dlala, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Tunis El Manar (UTM), Hôpital La Rabta [Tunis], Hôpital Nord [CHU - APHM], Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Ministry of Higher Education and Scientific Research of Tunisia, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital de la Timone [CHU - APHM] (TIMONE), HAL AMU, Administrateur, and Leroyer, Aurelie

Subjects
Adult, Male, 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Cell, lcsh:Medicine, Autoimmunity, CD146 Antigen, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Rheumatic diseases, MESH: CD4(+) T-CELLS, SOLUBLE CD146, MARKER, IDENTIFICATION, IL-17, RECEPTORS, CYTOKINES, FORM, Fibrosis, RAR-related orphan receptor gamma, Pulmonary fibrosis, medicine, Humans, lcsh:Science, Aged, Scleroderma, Systemic, Multidisciplinary, business.industry, Interleukin-17, lcsh:R, Middle Aged, Nuclear Receptor Subfamily 1, Group F, Member 3, medicine.disease, Acquired immune system, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Immunology, Th17 Cells, CD146, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:Q, IL17A, business, Biomarkers, 030215 immunology
Abstract

International audience; Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage, excessive fibrosis and abnormal T cells immune-regulation. CD146 is an adhesion molecule essentially expressed in the vascular system, but also on TH17 lymphocytes. In view of the recently described role of CD146 in SSc, we hypothesized an involvement of CD146 positive TH17 cells in this disease. Compared to healthy controls, we showed that both soluble form of CD146 (sCD146), and IL17A levels were increased in patients with SSc with a positive correlation between both factors. A significant increase in TH17 cells attested by an increase of RORγT, IL17A mRNA and CD4+ IL17A+ cell was observed in patients with SSc. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with SSc and inversely correlated with pulmonary fibrosis. In vitro experiments showed an augmentation of the percentage of TH17 cells expressing CD146 after cell treatment with sCD146, suggesting that, in patients the increase of this sub-population could be the consequence of the sCD146 increase in serum. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response, opening the way for the generation of new tools for the management of SSc. Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in the skin and internal organs, vascular damage and immune dysfunction. Two major clinical subsets, namely limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) forms have been described according to the extent of skin fibrosis 1. Pulmonary fibrosis and pulmonary arterial hypertension (PAH), are the most serious complications and constitute currently the major causes of death 2,3. The study of new molecular targets is essential in the understanding of the physiopa-thology of the disease, and the establishment of new therapeutic strategies. Among them, CD146 has been recently proposed as a new molecular target in SSc 4. This cell adhesion molecule , also called MUC18 and MCAM, is a membrane glycoprotein belonging to the Immunoglobulin super family 5. It is ubiquitously distributed on endothelium 6,7 , with a preferential localization at the endothelial junction 7. CD146 is involved in several functions such as cell adhesion 8 , inflammation 9 , and angiogenesis through different signaling pathways 8. CD146 also exists as a soluble form (sCD146) in the blood, resulting from the proteolysis of the membrane form 9-11. In a mice model of SSc induced by bleomycin, we showed that mice lacking CD146 were more susceptible to develop skin fibrosis than wild type animal. Fibrosis development could be prevented by subcutaneous sCD146 injection. We also evidenced the involvement of Wnt pathway since CD146 deficiency was associated with an up-regulation of the canonical Wnt pathway, leading to the profibrotic state 4. The expression of CD146 is not restricted to the endothelium since it is also expressed on other cell types such as melanoma cells 12 , extra villous trophoblastic cells 13 and TH17 cells 14. TH17 cells are involved in the pathogenesis of several autoimmune diseases including SSc 15. These cells play a critical role in the pathogenesis of autoimmune diseases, leading to production of several cytokines as IL17A, IL22, IL21 and IL26 14. The retinoic acid receptor-related-orphan-receptor-gamma T (RORγT), is the key transcription factor required for TH17 cell

Published
2019

40. CD146 deficiency promotes plaque formation in a mouse model of atherosclerosis by enhancing RANTES secretion and leukocyte recruitment

Author

Marcel Blot-Chabaud, Aurélie S. Leroyer, Stéphane Robert, Michel Aurrand-Lions, Karima Moussouni, Alexandrine Foucault-Bertaud, Richard Bachelier, Benjamin Guillet, Muriel G. Blin, Nathalie Bardin, Samantha Fernandez, Françoise Dignat-George, Karim Fallague, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Langage, LAngues et Cultures d'Afrique Noire (LLACAN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National des Langues et Civilisations Orientales (Inalco), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National des Langues et Civilisations Orientales (Inalco)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Leroyer, Aurelie, and BERNARD, Stéphanie

Subjects
0301 basic medicine, Apolipoprotein E, Mice, Knockout, ApoE, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Mice, 0302 clinical medicine, Chemokine CCL5, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Plaque, Atherosclerotic, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, CD146, medicine.symptom, Cardiology and Cardiovascular Medicine, réponse inflammatoire, medicine.medical_specialty, Médecine humaine et pathologie, Peritonitis, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, macrophage, CD146 Antigen, 03 medical and health sciences, Peritoneal cavity, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Animals, leucocyte, Molecular Biology, cavite peritoneale, business.industry, Macrophages, athérosclérose, système vasculaire, molécule d'adhésion, Atherosclerosis, medicine.disease, Neutrophilia, 030104 developmental biology, Atheroma, Endocrinology, Human health and pathology, protéine rantes, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Aims: The progression of atherosclerosis is based on the continued recruitment of leukocytes in the vessel wall. The previously described role of CD146 in leukocyte infiltration suggests an involvement for this adhesion molecule in the inflammatory response. In this study, we investigated the role of CD146 in leukocyte recruitment by using an experimental model of atherogenesis.Methods and results: The role of CD146 was explored in atherosclerosis by crossing CD146-/- mice with ApoE-/- mice. CD146 -/-/ApoE -/- and ApoE -/- mice were fed a Western diet for 24 weeks and were monitored for aortic wall thickness using high frequency ultrasound. The arterial wall was significantly thicker in CD146-deficient mice. After 24 weeks of Western diet, a significant increase of atheroma in both total aortic lesion and aortic sinus of CD146-null mice was observed. In addition, atherosclerotic lesions were more inflammatory since plaques from CD146-deficient mice contained more neutrophils and macrophages. This was due to up-regulation of RANTES secretion by macrophages in CD146-deficient atherosclerotic arteries. This prompted us to further address the function of CD146 in leukocyte recruitment during acute inflammation by using a second experimental model of peritonitis induced by thioglycollate. Neutrophil recruitment was significantly increased in CD146-deficient mice 12 h after peritonitis induction and associated with higher RANTES levels in the peritoneal cavity. In CD146-null macrophages, we also showed that increased RANTES production was dependent on constitutive inhibition of the p38-MAPK signaling pathway. Finally, Maraviroc, a RANTES receptor antagonist, was able to reduce atherosclerotic lesions and neutrophilia in CD146-deficient mice to the same level as that found in ApoE -/- mice.Conclusions: Our data indicate that CD146 deficiency is associated with the upregulation of RANTES production and increased inflammation of atheroma, which could influence the atherosclerotic plaque fate. Thus, these data identify CD146 agonists as potential new therapeutic candidates for atherosclerosis treatment.

Published
2019

41. Soluble CD146 boosts therapeutic effect of endothelial progenitors through proteolytic processing of short CD146 isoform

Author

Marcel Blot-Chabaud, Alexandrine Foucault-Bertaud, Françoise Dignat-George, Richard Bachelier, Karim Harhouri, Nathalie Bardin, Philippe Garrigue, Marie Nollet, Florence Sabatier, Alexandre Muller, Amel Essaadi, Benjamin Guillet, Aurélie S. Leroyer, Franck Peiretti, Lucas Hubert, Jimmy Stalin, Pascale Pisano, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Physiopathologie de l'Endothelium, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre Européen de Recherche en Imagerie médicale (CERIMED), Centre National de la Recherche Scientifique (CNRS)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-École Centrale de Marseille (ECM)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Biotherapie - Marseille, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU) - Assistance Publique - Hôpitaux de Marseille (APHM) - Ecole Centrale de Marseille (ECM) - Institut Paoli-Calmettes - Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Université de la Méditerranée - Aix-Marseille 2 - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), CIC Marseille, Université de la Méditerranée - Aix-Marseille 2 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Université de la Méditerranée - Aix-Marseille 2 - Institut National de la Recherche Agronomique (INRA) - Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche, santé, environnement et travail [Rennes] (Irset), Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'Immunologie [APHM-Hôpital de la Conception, Marseille], Assistance Publique - Hôpitaux de Marseille (APHM) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ) - Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Leroyer, Aurelie

Subjects
0301 basic medicine, Time Factors, Physiology, Angiogenesis, Fas-Associated Death Domain Protein, [SDV]Life Sciences [q-bio], Muscle Proteins, Apoptosis, Mice, 0302 clinical medicine, Cell Movement, Ischemia, Protein Isoforms, FADD, Phosphorylation, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Endothelial Progenitor Cells, biology, Hindlimb, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, Signal transduction, Cardiology and Cardiovascular Medicine, Signal Transduction, Matrix Metalloproteinases, Membrane-Associated, Nitric Oxide Synthase Type III, Endothelium, Cell Survival, bcl-X Protein, Neovascularization, Physiologic, CD146 Antigen, 03 medical and health sciences, Membrane Microdomains, Physiology (medical), Presenilin-1, medicine, Animals, Regeneration, Progenitor cell, Muscle, Skeletal, Intracellular part, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cell Proliferation, Endothelial progenitor, Vascular Endothelial Growth Factor Receptor-1, Kinase insert domain receptor, Vascular Endothelial Growth Factor Receptor-2, Angiomotin, ADAM Proteins, Disease Models, Animal, 030104 developmental biology, SPECT-CT, Proteolysis, biology.protein, Hindlimb ischaemia
Abstract

International audience; Aims: Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism.Methods and results: We investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo. In a mouse model of hindlimb ischaemia, the homing of radiolabelled cells to ischaemic tissue was assessed by SPECT-CT imaging. Soluble CD146 priming did not modify the number of engrafted ECFC but improved their survival capacity, leading to an enhanced revascularization. The mechanism of action of sCD146 on ECFC was studied in vitro. We showed that sCD146 acts in ECFC through a signalosome, located in lipid rafts, containing angiomotin, the short isoform of CD146 (shCD146), VEGFR1, VEGFR2, and presenilin-1. Soluble CD146 induced a sequential proteolytic cleavage of shCD146, with an extracellular shedding followed by an intramembrane cleavage mediated by matrix metalloprotease (MMP)/ADAM and presenilin-1, respectively. The generated intracellular part of shCD146 was directed towards the nucleus where it associated with the transcription factor CSL and modulated the transcription of genes involved in cell survival (FADD, Bcl-xl) and angiogenesis (eNOS). This effect was dependent on both VEGFR1 and VEGFR2, which were rapidly phosphorylated by sCD146.Conclusions: These findings establish that activation of the proteolytic processing of shCD146, in particular by sCD146, constitutes a promising pathway to improve endothelial progenitors' regenerative properties for the treatment of cardiovascular diseases.

Published
2016

42. Soluble CD146 cooperates with VEGF-A to generate an immunosuppressive microenvironment in CD146-positive tumors: interest of a combined antibody-based therapy.

Author

Joshkon A, Traboulsi W, Terme M, Bachelier R, Fayyad-Kazan H, Dignat-George F, Foucault-Bertaud A, Leroyer AS, Bardin N, and Blot-Chabaud M

Abstract

Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting Immune Checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICP, necessitating to further study the underlying mechanisms of exhaustion. Vascular Endothelial Growth Factor a (VEGFa), a pro-angiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICP, justifying in part the use of an anti-VEGFa monoclonal antibody (mAb), bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICP. In addition, sCD146 favors pro-tumoral M2-type macrophages and induces the secretion of pro-inflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.

Published
2024
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43. Microparticles and sudden cardiac death due to coronary occlusion. The TIDE (Thrombus and Inflammation in sudden DEath) study.

Author

Empana JP, Boulanger CM, Tafflet M, Renard JM, Leroyer AS, Varenne O, Prugger C, Silvain J, Tedgui A, Cariou A, Montalescot G, Jouven X, and Spaulding C

Subjects
Aged, Coronary Occlusion pathology, Coronary Thrombosis pathology, Death, Sudden, Cardiac pathology, Female, Humans, Male, Middle Aged, Myocardial Infarction etiology, Myocardial Infarction pathology, Prospective Studies, Cell-Derived Microparticles pathology, Coronary Occlusion complications, Coronary Thrombosis etiology, Death, Sudden, Cardiac etiology
Abstract

Aims: The pattern of coronary occlusion might contribute to the onset of ventricular arrhythmia and sudden cardiac death (SCD). We hypothesized that the concentrations of microparticles might differ between SCD and ST-elevation myocardial infarction (STEMI) patients without rhythmic disturbances., Methods and Results: The study sample includes consecutive patients hospitalized in two French tertiary centres between 2006 and 2011 for SCD with angiographically-proven acute coronary occlusion (n=23), for STEMI (n=61) and for a planned percutaneous coronary angioplasty (PCI) (n=35, controls). During PCI blood was collected in the arch of aorta (systemic blood) before and after the procedure and in the culprit coronary lesion with an aspiration catheter. Microparticles were analysed by flow cytometry in a blinded manner to quantify endothelial (CD144+), platelet (CD41+), leucocyte (CD11a+) and erythrocyte (CD235a+) derived microparticles. After multivariate analysis, intracoronary concentrations of endothelial-derived microparticles were significantly higher in SCD than in STEMI patients (129 (74-185) vs. 50 (21-118) nb/µl; p < 0.01). Intracoronary and systemic blood concentrations of platelet-derived microparticles were not different between SCD and controls, suggesting limited impact of cardiac massage and electric defibrillation in microparticle concentrations., Conclusion: The higher concentrations of endothelial-derived microparticles in SCD due to acute coronary occlusion compared with STEMI without rhythmic disturbances suggests different patterns of acute coronary occlusion., (© The European Society of Cardiology 2014.)

Published
2015
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44. Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis.

Author

Lacroix R, Plawinski L, Robert S, Doeuvre L, Sabatier F, Martinez de Lizarrondo S, Mezzapesa A, Anfosso F, Leroyer AS, Poullin P, Jourde N, Njock MS, Boulanger CM, Anglés-Cano E, and Dignat-George F

Subjects
Cardiovascular Diseases pathology, Case-Control Studies, Cells, Cultured, Endothelium, Vascular metabolism, Enzyme-Linked Immunosorbent Assay, Fibrinolysin metabolism, Flow Cytometry, Humans, Leukocytes metabolism, Purpura, Thrombotic Thrombocytopenic pathology, Renal Artery cytology, Renal Artery metabolism, Tissue Plasminogen Activator metabolism, Urokinase-Type Plasminogen Activator metabolism, Cardiovascular Diseases blood, Cell-Derived Microparticles metabolism, Endothelium, Vascular pathology, Fibrinolysis physiology, Leukocytes pathology, Purpura, Thrombotic Thrombocytopenic blood
Abstract

Background: We recently assigned a new fibrinolytic function to cell-derived microparticles in vitro. In this study we explored the relevance of this novel property of microparticles to the in vivo situation., Design and Methods: Circulating microparticles were isolated from the plasma of patients with thrombotic thrombocytopenic purpura or cardiovascular disease and from healthy subjects. Microparticles were also obtained from purified human blood cell subpopulations. The plasminogen activators on microparticles were identified by flow cytometry and enzyme-linked immunosorbent assays; their capacity to generate plasmin was quantified with a chromogenic assay and their fibrinolytic activity was determined by zymography., Results: Circulating microparticles isolated from patients generate a range of plasmin activity at their surface. This property was related to a variable content of urokinase-type plasminogen activator and/or tissue plasminogen activator. Using distinct microparticle subpopulations, we demonstrated that plasmin is generated on endothelial and leukocyte microparticles, but not on microparticles of platelet or erythrocyte origin. Leukocyte-derived microparticles bear urokinase-type plasminogen activator and its receptor whereas endothelial microparticles carry tissue plasminogen activator and tissue plasminogen activator/inhibitor complexes., Conclusions: Endothelial and leukocyte microparticles, bearing respectively tissue plasminogen activator or urokinase-type plasminogen activator, support a part of the fibrinolytic activity in the circulation which is modulated in pathological settings. Awareness of this blood-borne fibrinolytic activity conveyed by microparticles provides a more comprehensive view of the role of microparticles in the hemostatic equilibrium.

Published
2012
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45. Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles.

Author

Caporali A, Pani E, Horrevoets AJ, Kraenkel N, Oikawa A, Sala-Newby GB, Meloni M, Cristofaro B, Graiani G, Leroyer AS, Boulanger CM, Spinetti G, Yoon SO, Madeddu P, and Emanueli C

Subjects
Animals, Cells, Cultured, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental pathology, Disease Models, Animal, Endothelium, Vascular pathology, Humans, Ischemia etiology, Ischemia pathology, Male, Mice, Mice, Inbred Strains, Nitric Oxide metabolism, Nitric Oxide Synthase metabolism, Proto-Oncogene Proteins c-akt metabolism, Receptor, Nerve Growth Factor genetics, Signal Transduction physiology, Streptozocin, Transfection, Vascular Endothelial Growth Factor A metabolism, Apoptosis physiology, Diabetic Angiopathies metabolism, Endothelium, Vascular physiology, Ischemia metabolism, Muscle, Skeletal blood supply, Neovascularization, Physiologic physiology, Receptor, Nerve Growth Factor metabolism
Abstract

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75(NTR)), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75(NTR) expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75(NTR) gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75(NTR) depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75(NTR). Collectively, our data newly demonstrate the antiangiogenic action of p75(NTR) and open new avenues for the therapeutic use of p75(NTR) inhibition to combat diabetes-induced microvascular liabilities.

Published
2008
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