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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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.
The authors declare no competing financial interests.
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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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