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: Federico Carbone, Lindsey A Crowe, Aline Roth, Fabienne Burger, Sébastien Lenglet, Vincent Braunersreuther, Karim J Brandt, Alessandra Quercioli, François Mach, Jean-Paul Vallée, Fabrizio Montecucco
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 94 Pg. 82-94 (05 2016) ISSN: 1095-8584 [Electronic] England
• PMID: 27056420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Biomarkers
• Cytokines
• Inflammation Mediators
• RANK Ligand
• Troponin I

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Biomarkers
• Cell Degranulation
• Cytokines (blood, metabolism)
• Disease Models, Animal
• Inflammation Mediators (blood, metabolism)
• Lymphocyte Subsets (pathology)
• Macrophages (pathology)
• Magnetic Resonance Imaging
• Male
• Mice
• Myocardial Infarction (drug therapy, etiology, pathology, physiopathology)
• Myocardial Reperfusion Injury (drug therapy, metabolism, pathology, physiopathology)
• Neutrophil Infiltration
• Neutrophils (drug effects, immunology, metabolism)
• Oxidative Stress (drug effects)
• RANK Ligand (antagonists & inhibitors, metabolism)
• Troponin I (blood, metabolism)
• Ventricular Dysfunction (drug therapy)