The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis

Eur Heart J. 2015 Nov 7;36(42):2909-19. doi: 10.1093/eurheartj/ehv321. Epub 2015 Jul 22.


Aims: Viral myocarditis (VM) is an important cause of heart failure and sudden cardiac death in young healthy adults; it is also an aetiological precursor of dilated cardiomyopathy. We explored the role of the miR-221/-222 family that is up-regulated in VM.

Methods and results: Here, we show that microRNA-221 (miR-221) and miR-222 levels are significantly elevated during acute VM caused by Coxsackievirus B3 (CVB3). Both miRs are expressed by different cardiac cells and by infiltrating inflammatory cells, but their up-regulation upon myocarditis is mostly exclusive for the cardiomyocyte. Systemic inhibition of miR-221/-222 in mice increased cardiac viral load, prolonged the viraemic state, and strongly aggravated cardiac injury and inflammation. Similarly, in vitro, overexpression of miR-221 and miR-222 inhibited enteroviral replication, whereas knockdown of this miR-cluster augmented viral replication. We identified and confirmed a number of miR-221/-222 targets that co-orchestrate the increased viral replication and inflammation, including ETS1/2, IRF2, BCL2L11, TOX, BMF, and CXCL12. In vitro inhibition of IRF2, TOX, or CXCL12 in cardiomyocytes significantly dampened their inflammatory response to CVB3 infection, confirming the functionality of these targets in VM and highlighting the importance of miR-221/-222 as regulators of the cardiac response to VM.

Conclusions: The miR-221/-222 cluster orchestrates the antiviral and inflammatory immune response to viral infection of the heart. Its inhibition increases viral load, inflammation, and overall cardiac injury upon VM.

Keywords: Adverse inflammation; Coxsackievirus B3; Dilated cardiomyopathy; Myocarditis; Viral replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coxsackievirus Infections / immunology
  • Coxsackievirus Infections / virology*
  • Humans
  • Immunity, Cellular / immunology
  • Macrophages / immunology
  • Male
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Myocarditis / immunology
  • Myocarditis / virology*
  • Myocytes, Cardiac / immunology
  • T-Lymphocytes / immunology
  • Up-Regulation
  • Viral Load / immunology
  • Virus Replication / immunology


  • MIRN221 microRNA, mouse
  • MIRN222 microRNA, mouse
  • MicroRNAs