Skip to main content
SpringerLink
Log in

B Cells Increase Myocardial Inflammation by Suppressing M2 Macrophage Polarization in Coxsackie Virus B3-Induced Acute Myocarditis

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The role of B cells in viral myocarditis (VMC) remains controversial. In order to establish a role and mechanism of action for B cells in acute VMC, we established an acute VMC mouse model by intraperitoneal injection of Coxsackie virus group B type 3 (CVB3). At day 7, mice were analyzed using myocardial histopathology, and the presence of M2 macrophages in spleen and heart. Mice were divided into four groups, all having a C57BL/6 background: control group; wild-type (WT) VMC; mMt/mMt (−/−) VMC (BKO), and BKO + B cell VMC. A role for B cells was demonstrated by a significant reduction in myocardial pathological score and an increase in the frequency of M2 macrophages in the BKO group, when compared to the WT group. Once BKO mice underwent B cell reconstitution with isolated WT B cells, the myocardial pathological score was increased significantly, while the frequency of M2 macrophages decrease. Our findings demonstrate that B cells increase myocardial inflammation by suppressing M2 polarization in acute VMC in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Rose, N.R. 2016. Viral myocarditis. Current Opinion in Rheumatology 28 (4): 383–389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Trachtenberg, B.H., and J.M. Hare. 2017. Inflammatory cardiomyopathic syndromes. Circulation Research 121 (7): 803–818.

    Article  CAS  PubMed  Google Scholar 

  3. Fung, G., H. Luo, Y. Qiu, D. Yang, and B. McManus. 2016. Myocarditis. Circulation Research 118 (3): 496–514.

    Article  CAS  PubMed  Google Scholar 

  4. Taqueti, V.R., R.N. Mitchell, and A.H. Lichtman. 2006. Protecting the pump: controlling myocardial inflammatory responses. Annual Review of Physiology 68: 67–95.

    Article  CAS  PubMed  Google Scholar 

  5. Yue, Y., J. Gui, W. Xu, and S. Xiong. 2011. Gene therapy with CCL2 (MCP-1) mutant protects CVB3-induced myocarditis by compromising Th1 polarization. Molecular Immunology 48 (4): 706–713.

    Article  CAS  PubMed  Google Scholar 

  6. Abston, E.D., et al. 2012. Th2 regulation of viral myocarditis in mice: different roles for TLR3 versus TRIF in progression to chronic disease. Clinical & Developmental Immunology 2012: 129486.

    Article  Google Scholar 

  7. Qing, K., et al. 2011. Distinct different expression of Th17 and Th9 cells in coxsackie virus B3-induced mice viral myocarditis. Virology Journal 8: 267.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kong, Q., et al. 2012. Increased expressions of IL-22 and Th22 cells in the coxsackievirus B3-induced mice acute viral myocarditis. Virology Journal 9: 232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Takada, H., C. Kishimoto, and Y. Hiraoka. 1995. Therapy with immunoglobulin suppresses myocarditis in a murine coxsackievirus B3 model. Antiviral and anti-inflammatory effects. Circulation 92 (6): 1604–1611.

    Article  CAS  PubMed  Google Scholar 

  10. Li, R., et al. 2015. Cytokine-defined B cell responses as therapeutic targets in multiple sclerosis. Frontiers in Immunology 6: 626.

    Article  PubMed  Google Scholar 

  11. Zouggari, Yasmine, Hafid Ait-Oufella, Philippe Bonnin, Tabassome Simon, Andrew P. Sage, Coralie Guérin, José Vilar, Giuseppina Caligiuri, Dimitrios Tsiantoulas, Ludivine Laurans, Edouard Dumeau, Salma Kotti, Patrick Bruneval, Israel F. Charo, Christoph J. Binder, Nicolas Danchin, Alain Tedgui, Thomas F. Tedder, Jean-Sébastien Silvestre, and Ziad Mallat. 2013. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nature Medicine 19: 1273–1280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yanlan, H., et al. 2018. CD80 regulates Th17 cell differentiation in Coxsackie virus B3-induced acute myocarditis. Inflammation 41 (1): 232–239.

    Article  Google Scholar 

  13. Eriksson, U., R. Ricci, L. Hunziker, M.O. Kurrer, G.Y. Oudit, T.H. Watts, I. Sonderegger, K. Bachmaier, M. Kopf, and J.M. Penninger. 2003. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nature Medicine 9: 1484–1490.

    Article  CAS  PubMed  Google Scholar 

  14. Rudolph, V., R.P. Andrié, T.K. Rudolph, K. Friedrichs, A. Klinke, B. Hirsch-Hoffmann, A.P. Schwoerer, D. Lau, X.M. Fu, K. Klingel, K. Sydow, M. Didié, A. Seniuk, E.C. von Leitner, K. Szoecs, J.W. Schrickel, H. Treede, U. Wenzel, T. Lewalter, G. Nickenig, W.H. Zimmermann, T. Meinertz, R.H. Böger, H. Reichenspurner, B.A. Freeman, T. Eschenhagen, H. Ehmke, S.L. Hazen, S. Willems, and S. Baldus. 2010. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nature Medicine 16: 470–474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao, X., B. Wei, Y. Deng, Y.L. Huang, and W. Wu. 2017. Increased mobilization of CD45+CD34+VLA-4+ cells in acute viral myocarditis induced by coxsackievirus B3. Cardiology 138: 238–248.

    Article  CAS  PubMed  Google Scholar 

  16. Yu, M., S. Wen, M. Wang, W. Liang, H.H. Li, Q. Long, H.P. Guo, Y.H. Liao, and J. Yuan. 2013. TNF-α-secreting B cells contribute to myocardial fibrosis in dilated cardiomyopathy. Journal of Clinical Immunology 33 (5): 1002–1008.

    Article  CAS  PubMed  Google Scholar 

  17. Cen, Z., Y. Guo, Q. Kong, Q. Zhou, and W. Wu. 2015. IL-10-producing B cells involved in the pathogenesis of Coxsackie virus B3-induced acute viral myocarditis. International Journal of Clinical and Experimental Pathology 8 (1): 830–835.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lund, Frances E., et al. 2010. Effector and regulatory B cells: modulators of CD4 + T cell immunity. Nature Reviews Immunology 10 (4): 236–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Epelman, Slava, Peter P. Liu, and Douglas L. Mann. 2015. Role of innate and adaptive immunity in cardiac injury and repair. Nature Reviews Immunology 15 (2): 117–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Warwick, C.A., et al. 2017. Culture, transfection, and immunocytochemical analysis of primary macrophages. Methods in Molecular Biology 1554: 161–173.

    Article  CAS  PubMed  Google Scholar 

  21. Martinez, F.O., et al. 2008. Macrophage activation and polarization. Frontiers in Bioscience- Landmark 13: 453–461.

    Article  CAS  Google Scholar 

  22. Li, K., W. Xu, Q. Guo, Z. Jiang, P. Wang, Y. Yue, and S. Xiong. 2009. Differential macrophage polarization in male and female BALB/c mice infected with coxsackievirus B3 defines susceptibility to viral myocarditis. Circulation Research 105 (4): 353–364.

    Article  CAS  PubMed  Google Scholar 

  23. Locati, M., et al. 2013. Macrophage activation and polarization as an adaptive component of innate immunity. Advances in Immunology 120: 163–184.

    Article  CAS  PubMed  Google Scholar 

  24. Bermejo, Daniela A., et al. 2013. Trypanosoma cruzi trans-sialidase initiates an ROR-γt–AHR-independent program leading to IL-17 production by activated B cells. Nature Immunology 14 (5): 514–522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ireland, S.J., et al. 2016. B cells from relapsing remitting multiple sclerosis patients support neuro-antigen-specific Th17 responses. Journal of Neuroimmunology 15 (291): 46–53.

    Article  Google Scholar 

  26. Wong, Siew-Cheng, Anne-Laure Puaux, Manesh Chittezhath, Irina Shalova, Tasneem S. Kajiji, Xiaojie Wang, Jean-Pierre Abastado, Kong-Peng Lam, and Subhra K. Biswas. 2010. Macrophage polarization to a unique phenotype driven by B cells. European Journal of Immunology 40: 2296–2307.

    Article  CAS  PubMed  Google Scholar 

  27. Leuschner, Florian, Gabriel Courties, Partha Dutta, Luke J. Mortensen, Rostic Gorbatov, Brena Sena, Tatiana I. Novobrantseva, Anna Borodovsky, Kevin Fitzgerald, Victor Koteliansky, Yoshiko Iwamoto, Marina Bohlender, Soeren Meyer, Felix Lasitschka, Benjamin Meder, Hugo A. Katus, Charles Lin, Peter Libby, Filip K. Swirski, Daniel G. Anderson, Ralph Weissleder, and Matthias Nahrendorf. 2015. Silencing of CCR2 in myocarditis. European Heart Journal 36: 1478–1488.

    Article  CAS  PubMed  Google Scholar 

  28. Hauser, S.L., E. Waubant, D.L. Arnold, T. Vollmer, J. Antel, R.J. Fox, A. Bar-Or, M. Panzara, N. Sarkar, S. Agarwal, A. Langer-Gould, C.H. Smith, and HERMES Trial Group. 2008. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. New England Journal of Medicine 358 (7): 676–688.

    Article  CAS  PubMed  Google Scholar 

  29. Cambridge, G., H.C. Perry, L. Nogueira, G. Serre, H.M. Parsons, I. de la Torre, M.C. Dickson, M.J. Leandro, and J.C.W. Edwards. 2014. The effect of B-cell depletion therapy on serological evidence of B-cell and plasmablast activation in patients with rheumatoid arthritis over multiple cycles of rituximab treatment. Journal of Autoimmunity 50: 67–76.

    Article  CAS  PubMed  Google Scholar 

  30. Sangle, S.R., P.M.K. Lutalo, R.J. Davies, M.A. Khamashta, and D.P. D'Cruz. 2013. B-cell depletion therapy and pregnancy outcome in severe, refractory systemic autoimmune diseases. Journal of Autoimmunity 43: 55–59.

    Article  CAS  PubMed  Google Scholar 

  31. Fleischer, V., J. Sieber, S.J. Fleischer, A. Shock, G. Heine, C. Daridon, and T. Dörner. 2015. Epratuzumab inhibits the production of the proinflammatory cytokines IL-6 and TNF-α, but not the regulatory cytokine IL-10, by B cells from healthy donors and SLE patients. Arthritis Research & Therapy 17: 185.

    Article  Google Scholar 

Download references

Funding

This study was funded by the National Natural Science Foundation of China (81670345).

Author information

Author notes

  1. Yong Li and Yanlan Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, People’s Republic of China

    Yong Li, Yanlan Huang, Weifeng Wu, Bin Wei & Lin Qin

Authors
  1. Yong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanlan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weifeng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weifeng Wu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Huang, Y., Wu, W. et al. B Cells Increase Myocardial Inflammation by Suppressing M2 Macrophage Polarization in Coxsackie Virus B3-Induced Acute Myocarditis. Inflammation 42, 953–960 (2019). https://doi.org/10.1007/s10753-018-0950-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-018-0950-0

KEY WORDS

Search

Navigation