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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
White, H.D. & Chew, D.P. Acute myocardial infarction. Lancet 372, 570–584 (2008).
Jessup, M. & Brozena, S. Heart failure. N. Engl. J. Med. 348, 2007–2018 (2003).
McMurray, J.J. & Pfeffer, M.A. Heart failure. Lancet 365, 1877–1889 (2005).
Shah, A.M. & Mann, D.L. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378, 704–712 (2011).
Nabel, E.G. & Braunwald, E. A tale of coronary artery disease and myocardial infarction. N. Engl. J. Med. 366, 54–63 (2012).
Yellon, D.M. & Hausenloy, D.J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121–1135 (2007).
Taqueti, V.R., Mitchell, R.N. & Lichtman, A.H. Protecting the pump: controlling myocardial inflammatory responses. Annu. Rev. Physiol. 68, 67–95 (2006).
Zhang, M. et al. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury. Proc. Natl. Acad. Sci. USA 101, 3886–3891 (2004).
Zhang, M. et al. Identification of the target self-antigens in reperfusion injury. J. Exp. Med. 203, 141–152 (2006).
Zhang, M. et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J. Immunol. 177, 4727–4734 (2006).
Haas, M.S. et al. Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction. Cardiovasc. Res. 87, 618–627 (2010).
Renner, B. et al. B cell subsets contribute to renal injury and renal protection after ischemia/reperfusion. J. Immunol. 185, 4393–4400 (2010).
Pepys, M.B. et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440, 1217–1221 (2006).
Salio, M. et al. Cardioprotective function of the long pentraxin PTX3 in acute myocardial infarction. Circulation 117, 1055–1064 (2008).
Granger, D.N. & Korthuis, R.J. Physiologic mechanisms of postischemic tissue injury. Annu. Rev. Physiol. 57, 311–332 (1995).
Vinten-Johansen, J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc. Res. 61, 481–497 (2004).
Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).
Leuschner, F. et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J. Exp. Med. 209, 123–137 (2012).
Mahaffey, K.W. et al. Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction: the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial. Circulation 108, 1176–1183 (2003).
Granger, C.B. et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. Circulation 108, 1184–1190 (2003).
Armstrong, P.W. et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. J. Am. Med. Assoc. 297, 43–51 (2007).
Eikelboom, J.W. & O'Donnell, M. Pexelizumab does not “complement” percutaneous coronary intervention in patients with ST-elevation myocardial infarction. J. Am. Med. Assoc. 297, 91–92 (2007).
Martin, F. & Chan, A.C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).
Uchida, J. et al. Mouse CD20 expression and function. Int. Immunol. 16, 119–129 (2004).
Ait-Oufella, H. et al. B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207, 1579–1587 (2010).
Hamaguchi, Y. et al. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J. Immunol. 174, 4389–4399 (2005).
Busche, M.N., Pavlov, V., Takahashi, K. & Stahl, G.L. Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. Am. J. Physiol. Heart Circ. Physiol. 297, H1853–H1859 (2009).
Tsou, C.L. et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J. Clin. Invest. 117, 902–909 (2007).
Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).
Kelly-Scumpia, K.M. et al. B cells enhance early innate immune responses during bacterial sepsis. J. Exp. Med. 208, 1673–1682 (2011).
Rauch, P.J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012).
Yilmaz, G., Arumugam, T.V., Stokes, K.Y. & Granger, D.N. Role of T lymphocytes and interferon-γ in ischemic stroke. Circulation 113, 2105–2112 (2006).
Burne-Taney, M.J. et al. B cell deficiency confers protection from renal ischemia reperfusion injury. J. Immunol. 171, 3210–3215 (2003).
Jang, H.R. et al. B cells limit repair after ischemic acute kidney injury. J. Am. Soc. Nephrol. 21, 654–665 (2010).
Goodchild, T.T. et al. Bone marrow–derived B cells preserve ventricular function after acute myocardial infarction. JACC Cardiovasc. Interv. 2, 1005–1016 (2009).
Kyaw, T. et al. Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J. Immunol. 185, 4410–4419 (2010).
Sage, A.P. et al. BAFF receptor deficiency reduces the development of atherosclerosis in mice—brief report. Arterioscler. Thromb. Vasc. Biol. 32, 1573–1576 (2012).
Kyaw, T. et al. Depletion of B2 but not B1a B cells in BAFF receptor–deficient ApoE mice attenuates atherosclerosis by potently ameliorating arterial inflammation. PLoS ONE 7, e29371 (2012).
Yanaba, K. et al. B-lymphocyte contributions to human autoimmune disease. Immunol. Rev. 223, 284–299 (2008).
Togbe, D. et al. Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways. Lab. Invest. 86, 1126–1135 (2006).
Kumar, D. et al. Distinct mouse coronary anatomy and myocardial infarction consequent to ligation. Coron. Artery Dis. 16, 41–44 (2005).
Scholz, J.L. et al. BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact. Proc. Natl. Acad. Sci. USA 105, 15517–15522 (2008).
Cochain, C. et al. Regulation of monocyte subset systemic levels by distinct chemokine receptors controls post-ischaemic neovascularization. Cardiovasc. Res. 88, 186–195 (2010).
Simon, T. et al. Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med. 360, 363–375 (2009).
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
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–13 and Supplementary Tables 1 and 2 (PDF 6824 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3284
This article is cited by
-
Association of systemic inflammatory response index with ST segment elevation myocardial infarction and degree of coronary stenosis: a cross-sectional study
BMC Cardiovascular Disorders (2024)
-
Integrating MXene/MWCNTs into aptasensor capable of ultrasensitive quantification of cTnI towards the diagnosis of acute myocardial infarction
Chemical Papers (2024)
-
Cardiovascular Disease in Anti-neutrophil Cytoplasm Antibody-Associated Vasculitis
Current Rheumatology Reports (2024)
-
Murine neonatal cardiac B cells promote cardiomyocyte proliferation and heart regeneration
npj Regenerative Medicine (2023)
-
Inflammatory cells dynamics control neovascularization and tissue healing after localized radiation induced injury in mice
Communications Biology (2023)