title: Treatment with anti-RANKL antibody reduces infarct size and attenuates dysfunction impacting on neutrophil-mediated injury.
abstract: Selective pharmacological treatments targeting reperfusion injury produced modest protective effects and might be associated with immunosuppression. In order to identify novel and better-tolerated approaches, we focused on the neutralization of receptor activator of nuclear factor kappa-B ligand [RANKL], a cytokine recently shown to activate inflammatory cells (i.e. neutrophils) orchestrating post-infarction injury and repair. Myocardial ischemia (60min) and reperfusion injury was surgically induced in C57Bl/6 mice. In hearts and serum, RANKL was early upregulated during reperfusion. A "one-shot" injection with neutralizing anti-RANKL IgG during ischemia ameliorated myocardial infarct size and function, but not adverse remodeling (determined by Magnetic Resonance Imaging [MRI]) as compared to Vehicle or control IgG. These beneficial effects were accompanied in vivo by reduction in cardiac neutrophil infiltration, reactive oxygen species (ROS) and MMP-9 release. Anti-RANKL IgG treatment suppressed sudden peak of neutrophil granule products in mouse serum early after reperfusion onset. In vitro, RANK mRNA expression was detected in isolated mouse neutrophils. Co-incubation with neutralizing anti-RANKL IgG abrogated RANKL-induced mouse neutrophil degranulation and migration, suggesting a critical role of RANKL in neutrophil-mediated injury. Conversely, anti-RANKL IgG did not affect salvage pathways in cardiac cells (i.e. ERK p42/p44, Akt and STAT-3) or macrophage cardiac infiltration. Finally, treatment with anti-RANKL IgG showed no effect on B and T lymphocyte polarization (in serum, spleen and infarcted myocardium) and circulating chemokines as compared with Vehicle or control IgG. In conclusion, acute treatment with anti-RANKL IgG improved cardiac infarct size and function by potentially impacting on neutrophil-mediated injury and repair.
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Carbone
authors.affiliation: Division of Radiology, Geneva University Hospital and Faculty of Medicine, 1205 Geneva, Switzerland.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Crowe
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Roth
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.affiliation: Division of Pathology, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Karim J
authors.initials: KJ
authors.lastname: Brandt
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Quercioli
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, Faculty of Medicine, Department of Internal Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.affiliation: Division of Radiology, Geneva University Hospital and Faculty of Medicine, 1205 Geneva, Switzerland.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vallée
authors.affiliation: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine and IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, 6 viale Benedetto XV, 16132 Genoa, Italy. Electronic address: Fabrizio.montecucco@unige.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015415:Biomarkers; D015550:Cell Degranulation; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019210:Troponin I / Q000097:blood / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D053245:RANK Ligand; D019210:Troponin I
keywords: Inflammation; Myocardial infarction; Neutrophils