SpringerLink
Log in

Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Adiponectin (APN) is an immunomodulatory adipocytokine that improves outcome in patients with virus-negative inflammatory cardiomyopathy and mice with autoimmune myocarditis. Here, we investigated whether APN modulates cardiac inflammation and injury in coxsackievirus B3 (CVB3) myocarditis. Myocarditis was induced by CVB3 infection of APN-KO and WT mice. APN reconstitution was performed by adenoviral gene transfer. Expression analyses were performed by qRT-PCR and immunoblot. Cardiac histology was analyzed by H&E-stain and immunohistochemistry. APN-KO mice exhibited diminished subacute myocarditis with reduced viral load, attenuated inflammatory infiltrates determined by NKp46, F4/80 and CD3/CD4/CD8 expression and reduced IFNβ, IFNγ, TNFα, IL-1β and IL-12 levels. Moreover, myocardial injury assessed by necrotic lesions and troponin I release was attenuated resulting in preserved left ventricular function. Those changes were reversed by APN reconstitution. APN had no influence on adhesion, uptake or replication of CVB3 in cardiac myocytes. In acute CVB3 myocarditis, cardiac viral load did not differ between APN-KO and WT mice. However, APN-KO mice displayed an enhanced acute immune response, i.e. increased expression of myocardial CD14, IFNβ, IFNγ, IL-12, and TNFα resulting in increased cardiac infiltration with pro-inflammatory M1 macrophages and activated NK cells. Up-regulation of cardiac CD14 expression, type I and II IFNs and inflammatory cell accumulation in APN-KO mice was inhibited by APN reconstitution. Our observations indicate that APN promotes CVB3 myocarditis by suppression of toll-like receptor-dependent innate immune responses, polarization of anti-inflammatory M2 macrophages and reduction of number and activation of NK cells resulting in attenuated acute anti-viral immune responses.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Badorff C, Lee GH, Lamphear BJ, Martone ME, Campbell KP, Rhoads RE, Knowlton KU (1999) Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nat Med 5:320–326. doi:10.1038/6543

    Article  CAS  PubMed  Google Scholar 

  2. Blyszczuk P, Kania G, Dieterle T, Marty RR, Valaperti A, Berthonneche C, Pedrazzini T, Berger CT, Dirnhofer S, Matter CM, Penninger JM, Luscher TF, Eriksson U (2009) Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ Res 105:912–920. doi:10.1161/CIRCRESAHA.109.199802

    Article  CAS  PubMed  Google Scholar 

  3. Bobbert P, Scheibenbogen C, Jenke A, Kania G, Wilk S, Krohn S, Stehr J, Kuehl U, Rauch U, Eriksson U, Schultheiss HP, Poller W, Skurk C (2011) Adiponectin expression in patients with inflammatory cardiomyopathy indicates favourable outcome and inflammation control. Eur Heart J 32:1134–1147. doi:10.1093/eurheartj/ehq498

    Article  CAS  PubMed  Google Scholar 

  4. Chiang CH, Lai JS, Hung SH, Lee LT, Sheu JC, Huang KC (2013) Serum adiponectin levels are associated with hepatitis B viral load in overweight to obese hepatitis B virus carriers. Obesity 21:291–296. doi:10.1002/oby.20000

    Article  CAS  PubMed  Google Scholar 

  5. Chow LH, Beisel KW, McManus BM (1992) Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury. Lab Invest 66:24–31

    CAS  PubMed  Google Scholar 

  6. Cooper LT Jr (2009) Myocarditis. N Eng J Med 360:1526–1538. doi:10.1056/NEJMra0800028

    Article  CAS  Google Scholar 

  7. Deonarain R, Cerullo D, Fuse K, Liu PP, Fish EN (2004) Protective role for interferon-beta in coxsackievirus B3 infection. Circulation 110:3540–3543. doi:10.1161/01.CIR.0000136824.73458.20

    Article  CAS  PubMed  Google Scholar 

  8. Esfandiarei M, McManus BM (2008) Molecular biology and pathogenesis of viral myocarditis. Annu Rev Pathol 3:127–155. doi:10.1146/annurev.pathmechdis.3.121806.151534

    Article  CAS  PubMed  Google Scholar 

  9. Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Steele RA, Gatewood SJ, Rose NR (2005) IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-gamma and macrophage and neutrophil populations in the heart. J Immunol 174:261–269

    Article  CAS  PubMed  Google Scholar 

  10. Finberg RW, Kurt-Jones EA (2006) CD14: chaperone or matchmaker? Immunity 24:127–129. doi:10.1016/j.immuni.2006.01.010

    Article  CAS  PubMed  Google Scholar 

  11. Fujiu K, Nagai R (2013) Contributions of cardiomyocyte–cardiac fibroblast–immune cell interactions in heart failure development. Basic Res Cardiol 108:1–15. doi:10.1007/s00395-013-0357-x

    Article  Google Scholar 

  12. Gebhard JR, Perry CM, Harkins S, Lane T, Mena I, Asensio VC, Campbell IL, Whitton JL (1998) Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol 153:417–428. doi:10.1016/S0002-9440(10)65585-X

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Godeny EK, Gauntt CJ (1986) Involvement of natural killer cells in coxsackievirus B3-induced murine myocarditis. J Immunol 137:1695–1702

    CAS  PubMed  Google Scholar 

  14. Gorbea C, Makar KA, Pauschinger M, Pratt G, Bersola JL, Varela J, David RM, Banks L, Huang CH, Li H, Schultheiss HP, Towbin JA, Vallejo JG, Bowles NE (2010) A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy. J Biol Chem 285:23208–23223. doi:10.1074/jbc.M109.047464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hofmann U, Frantz S (2013) How can we cure a heart “in flame”? A translational view on inflammation in heart failure. Basic Res Cardiol 108:1–19. doi:10.1007/s00395-013-0356-y

    Google Scholar 

  16. Jenke A, Wilk S, Poller W, Eriksson U, Valaperti A, Rauch BH, Stroux A, Liu P, Schultheiss HP, Scheibenbogen C, Skurk C (2013) Adiponectin protects against Toll-like receptor 4 mediated cardiac inflammation and injury. Cardiovasc Res 99:422–431. doi:10.1093/cvr/cvt118

    Article  CAS  PubMed  Google Scholar 

  17. Kanda T, Saegusa S, Takahashi T, Sumino H, Morimoto S, Nakahashi T, Iwai K, Matsumoto M (2007) Reduced-energy diet improves survival of obese KKAy mice with viral myocarditis: induction of cardiac adiponectin expression. Int J Cardiol 119:310–318. doi:10.1016/j.ijcard.2006.07.181

    Article  PubMed  Google Scholar 

  18. Kandolf R, Sauter M, Aepinus C, Schnorr JJ, Selinka HC, Klingel K (1999) Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system. Virus Res 62:149–158. doi:10.1016/S0168-1702(99)00041-6

    Article  CAS  PubMed  Google Scholar 

  19. Kania G, Blyszczuk P, Eriksson U (2009) Mechanisms of cardiac fibrosis in inflammatory heart disease. Trends Cardiovas Med 19:247–252. doi:10.1016/j.tcm.2010.02.005

    Article  CAS  Google Scholar 

  20. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bultmann B, Muller T, Lindinger A, Bohm M (2008) Predictors of outcome in patients with suspected myocarditis. Circulation 118:639–648. doi:10.1161/CIRCULATIONAHA.108.769489

    Article  PubMed  Google Scholar 

  21. Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M, Mall G, Kandolf R (1992) Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. PNAS 89:314–318. doi:10.1073/pnas.89.1.314

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Kuhl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, Poller W, Kandolf R, Schultheiss HP (2005) High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction. Circulation 111:887–893. doi:10.1161/01.CIR.0000155616.07901.35

    Article  PubMed  Google Scholar 

  23. Kuhl U, Pauschinger M, Schwimmbeck PL, Seeberg B, Lober C, Noutsias M, Poller W, Schultheiss HP (2003) Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 107:2793–2798. doi:10.1161/01.CIR.0000072766.67150.51

    Article  PubMed  Google Scholar 

  24. Lamphear BJ, Yan R, Yang F, Waters D, Liebig HD, Klump H, Kuechler E, Skern T, Rhoads RE (1993) Map** the cleavage site in protein synthesis initiation factor eIF-4 gamma of the 2A proteases from human Coxsackievirus and rhinovirus. J Biol Chem 268:19200–19203

    CAS  PubMed  Google Scholar 

  25. Meznarich J, Malchodi L, Helterline D, Ramsey SA, Bertko K, Plummer T, Plawman A, Gold E, Stempien-Otero A (2013) Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages. PLoS One 8:e57837. doi:10.1371/journal.pone.0057837

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Negishi H, Osawa T, Ogami K, Ouyang X, Sakaguchi S, Koshiba R, Yanai H, Seko Y, Shitara H, Bishop K, Yonekawa H, Tamura T, Kaisho T, Taya C, Taniguchi T, Honda K (2008) A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. PNAS 105:20446–20451. doi:10.1073/pnas.0810372105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Pedersen AA, Kalthoff C, Tullin S, Sams A, Summer R, Walsh K (2010) Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem 285:6153–6160. doi:10.1074/jbc.M109.088708

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102:1296–1301

    Article  CAS  PubMed  Google Scholar 

  29. Pei H, Qu Y, Lu X, Yu Q, Lian K, Liu P, Yan W, Liu J, Ma Y, Liu Y, Li C, Li W, Lau W, Zhang H, Tao L (2012) Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling. Basic Res Cardiol 108:1–11. doi:10.1007/s00395-012-0322-0

    Google Scholar 

  30. Porta C, Rimoldi M, Raes G, Brys L, Ghezzi P, Di Liberto D, Dieli F, Ghisletti S, Natoli G, De Baetselier P, Mantovani A, Sica A (2009) Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor kappaB. PNAS 106:14978–14983. doi:10.1073/pnas.0809784106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Riad A, Westermann D, Zietsch C, Savvatis K, Becher PM, Bereswill S, Heimesaat MM, Lettau O, Lassner D, Dorner A, Poller W, Busch M, Felix SB, Schultheiss HP, Tschope C (2011) TRIF is a critical survival factor in viral cardiomyopathy. J Immunol 186:2561–2570. doi:10.4049/jimmunol.1002029

    Article  CAS  PubMed  Google Scholar 

  32. Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS, Sam F, Ouchi N, Walsh K (2007) Adiponectin protects against the development of systolic dysfunction following myocardial infarction. J Mol Cell Cardiol 42:1065–1074. doi:10.1016/j.yjmcc.2007.03.808

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K, Funahashi T, Ouchi N, Walsh K (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11:1096–1103. doi:10.1038/nm1295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Takahashi T, Saegusa S, Sumino H, Nakahashi T, Iwai K, Morimoto S, Kanda T (2005) Adiponectin replacement therapy attenuates myocardial damage in leptin-deficient mice with viral myocarditis. Journal Int Med Res 33:207–214. doi:10.1177/147323000503300208

    Article  CAS  Google Scholar 

  35. Takahashi T, Yu F, Saegusa S, Sumino H, Nakahashi T, Iwai K, Morimoto S, Kurabayashi M, Kanda T (2006) Impaired expression of cardiac adiponectin in leptin-deficient mice with viral myocarditis. Int Heart J 47:107–123. doi:10.1536/ihj.47.107

    Article  CAS  PubMed  Google Scholar 

  36. Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783. doi:10.1038/nri1937

    Article  CAS  PubMed  Google Scholar 

  37. Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735–747. doi:10.1038/nri911

    Article  CAS  PubMed  Google Scholar 

  38. Wada H, Saito K, Kanda T, Kobayashi I, Fujii H, Fujigaki S, Maekawa N, Takatsu H, Fujiwara H, Sekikawa K, Seishima M (2001) Tumor necrosis factor-alpha (TNF-alpha) plays a protective role in acute viralmyocarditis in mice: a study using mice lacking TNF-alpha. Circulation 103:743–749

    Article  CAS  PubMed  Google Scholar 

  39. Wessely R, Klingel K, Knowlton KU, Kandolf R (2001) Cardioselective infection with coxsackievirus B3 requires intact type I interferon signaling: implications for mortality and early viral replication. Circulation 103:756–761

    Article  CAS  PubMed  Google Scholar 

  40. Wilk S, Jenke A, Stehr J, Yang CA, Bauer S, Goldner K, Kotsch K, Volk HD, Poller W, Schultheiss HP, Skurk C, Scheibenbogen C (2013) Adiponectin modulates natural killer cell function. Eur J Immunol 43:1024–1033. doi:10.1002/eji.201242382

    Article  CAS  PubMed  Google Scholar 

  41. Wilk S, Scheibenbogen C, Bauer S, Jenke A, Rother M, Guerreiro M, Kudernatsch R, Goerner N, Poller W, Elligsen-Merkel D, Utku N, Magrane J, Volk HD, Skurk C (2011) Adiponectin is a negative regulator of antigen-activated T cells. Eur J Immunol 41:2323–2332. doi:10.1002/eji.201041349

    Article  CAS  PubMed  Google Scholar 

  42. Woodruff JF, Woodruff JJ (1974) Involvement of T lymphocytes in the pathogenesis of coxsackie virus B3 heart disease. J Immunol 113:1726–1734

    CAS  PubMed  Google Scholar 

  43. **ong D, Lee GH, Badorff C, Dorner A, Lee S, Wolf P, Knowlton KU (2002) Dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy: a genetic predisposition to viral heart disease. Nat Med 8:872–877. doi:10.1038/nm737

    CAS  PubMed  Google Scholar 

  44. Yajima T, Knowlton KU (2009) Viral myocarditis: from the perspective of the virus. Circulation 119:2615–2624. doi:10.1161/CIRCULATIONAHA.108.766022

    Article  PubMed  Google Scholar 

  45. Yan W, Zhang H, Liu P, Wang H, Liu J, Gao C, Liu Y, Lian K, Yang L, Sun L, Guo Y, Zhang L, Dong L, Lau W, Gao E, Gao F, **ong L, Wang H, Qu Y, Tao L (2013) Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol 108:1–15. doi:10.1007/s00395-013-0329-1

    Article  Google Scholar 

  46. Yoon S, Jung J, Kim T, Park S, Chwae YJ, Shin HJ, Kim K (2011) Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor gamma, controls hepatitis B virus replication. Virology 409:290–298. doi:10.1016/j.virol.2010.10.024

    Article  CAS  PubMed  Google Scholar 

  47. Zacharioudaki V, Androulidaki A, Arranz A, Vrentzos G, Margioris AN, Tsatsanis C (2009) Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression. J Immunol 182:6444–6451. doi:10.4049/jimmunol.0803694

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant of Deutsche Forschungsgemeinschaft (SFB TR19, TP B7 to CS and CS as well as TP Z4 to KK).

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    A. Jenke, L. Holzhauser, K. Savvatis, A. Weithäuser, C. Tschöpe, W. Poller, H. P. Schultheiss & C. Skurk

  2. Institute of Medical Immunology, Charité University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany

    M. Löbel, S. Wilk & C. Scheibenbogen

  3. Biotechnological Institute, Technical University Berlin, Gustav-Meyer-Allee 25, 13355, Berlin, Germany

    S. Pinkert

  4. Department of Molecular Pathology, University of Tübingen, Liebermeisterstrasse 8, 72076, Tübingen, Germany

    K. Klingel

Authors
  1. A. Jenke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. Holzhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Löbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. Savvatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Wilk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Weithäuser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Pinkert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Tschöpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Klingel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. W. Poller
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C. Scheibenbogen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. H. P. Schultheiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C. Skurk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Skurk.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 kb)

Supplementary material 2 (PPT 639 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jenke, A., Holzhauser, L., Löbel, M. et al. Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses. Basic Res Cardiol 109, 408 (2014). https://doi.org/10.1007/s00395-014-0408-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-014-0408-y

Keywords

Search

Navigation