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

Maarten Corsten, Ward Heggermont, Anna-Pia Papageorgiou, Sophie Deckx, Aloys Tijsma, Wouter Verhesen, Rick van Leeuwen, Paolo Carai, Hendrik-Jan Thibaut, Kevin Custers, Georg Summer, Mark Hazebroek, Fons Verheyen, Johan Neyts, Blanche Schroen, Stephane Heymans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

67 Citations (Web of Science)

Abstract

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 upregulated 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 coorchestrate 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.
Original languageEnglish
Pages (from-to)2909-U56
JournalEuropean Heart Journal
Volume36
Issue number42
DOIs
Publication statusPublished - 7 Nov 2015

Keywords

  • Myocarditis
  • Coxsackievirus B3
  • Adverse inflammation
  • Dilated cardiomyopathy
  • Viral replication

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