B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction

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Abstract

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6Chi monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell–selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.

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Figure 1: The B cell–depleting CD20 mAb reduces infarct size, improves heart function and limits myocardial inflammation.
Figure 2: B lymphocyte depletion impairs monocyte mobilization and recruitment and macrophage accumulation in the injured myocardium.
Figure 3: B lymphocyte depletion significantly lowers Ccl7 concentrations after acute myocardial infarction and triggers Ccl7-dependent monocyte transmigration in vitro and in vivo.
Figure 4: B lymphocytes trigger adverse ventricular remodeling and alter heart function through the production of Ccl7.
Figure 5: Blockade of Baff signaling impairs monocyte mobilization and improves heart function after acute myocardial infarction.
Figure 6: Circulating levels of CCL7 and BAFF during the acute phase of myocardial infarction are associated with cardiovascular outcomes.

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Acknowledgements

This work was supported by INSERM, the British Heart Foundation (Z.M.), the European Research Council (Z.M.), Fondation Coeur et Recherche (Z.M., T.S. and N.D.), Fondation pour la Recherche Médicale (J.-S.S.), European Union Seven Framework programme TOLERAGE (Z.M.), Fondation Leducq Transatlantic Network (C.J.B., D.T., A.T., J.-S.S. and Z.M.), US National Institutes of Health grants AI56363 and AI057157, and a grant from The Lymphoma Research Foundation (T.F.T.). We are indebted to M.O. Kozma, L. Baker and J. Harrison for excellent technical assistance. The Baff-specific antibody was a kind gift from Human Genome Sciences. Myd88−/−; Trif−/− mice were provided by B. Ryffel (Unité Mixte de Recherche 7355, Orléans, France). Y.Z. is a recipient of fellowships from Fondation pour la Recherche Médicale and from Journées de Biologie Clinique. We thank the physicians who cared for the patients at the participating institutions, the International Clinical Trials Association Contract Research Organization (Fontaine-lès-Dijon, France), E. Drouet and the Clinical Research Assistant team of Unité de Recherche Clinique de l'Est Parisien (Assistance Publique–Hôpitaux de Paris and UPMC Paris 06), B. Pace, V. Bataille and G. Mulak (French Society of Cardiology) for their assistance in designing the electronic case-record form and data management during the follow-up period.

Author information

Y.Z. and H.A.-O. performed the experiments and acquired and interpreted the data. P. Bonnin performed and interpreted the ultrasound studies. T.S. and N.D. were responsible for the FAST-MI cohort and interpreted the statistical data. A.P.S. contributed to the Baff and Baff-r studies. C.G. contributed to flow cytometry analysis and interpretation. J.V. and E.D. contributed to data acquisition and analysis. G.C. and L.L. performed the biomarkers measurements. D.T. and C.J.B. were involved in antibody measurements and Baff-specific antibody experiments. S.K. performed the statistical analysis on the human data. P. Bruneval analyzed and interpreted the disease pathology. I.F.C. provided the Ccl7−/− mice. A.T. contributed to study design and data interpretation. T.F.T. generated and provided the CD20 mAb. J-S.S. and Z.M. designed the experiments, analyzed and interpreted the data. Y.Z., J.-S.S. and Z.M. wrote the manuscript.

Correspondence to Ziad Mallat.

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Zouggari, Y., Ait-Oufella, H., Bonnin, P. et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 19, 1273–1280 (2013). https://doi.org/10.1038/nm.3284

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