title: The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Corsten
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands Center for Molecular and Vascular Research, University of Leuven, Leuven B-3000, Belgium Department of Internal Medicine, Service of Cardiology, University Hospitals Leuven, Leuven B-3000, Belgium.
authors.forename: Ward
authors.initials: W
authors.lastname: Heggermont
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands Center for Molecular and Vascular Research, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Anna-Pia
authors.initials: AP
authors.lastname: Papageorgiou
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Sophie
authors.initials: S
authors.lastname: Deckx
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Aloys
authors.initials: A
authors.lastname: Tijsma
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Verhesen
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: van Leeuwen
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands Center for Molecular and Vascular Research, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carai
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Hendrik-Jan
authors.initials: HJ
authors.lastname: Thibaut
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: Custers
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Georg
authors.initials: G
authors.lastname: Summer
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Hazebroek
authors.affiliation: Electron Microscopy Unit, Maastricht University, Maastricht AZ-6202, The Netherlands.
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Leuven B-3000, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, P. Debyelaan 25, Maastricht AZ-6202, The Netherlands Center for Molecular and Vascular Research, University of Leuven, Leuven B-3000, Belgium s.heymans@maastrichtuniversity.nl.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000818:Animals; D003384:Coxsackievirus Infections / Q000276:immunology / Q000821:virology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009205:Myocarditis / Q000276:immunology / Q000821:virology*; D032383:Myocytes, Cardiac / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: C546122:MIRN221 microRNA, mouse; C546123:MIRN222 microRNA, mouse; D035683:MicroRNAs
keywords: Adverse inflammation; Coxsackievirus B3; Dilated cardiomyopathy; Myocarditis; Viral replication