TY - JOUR
T1 - The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis
AU - Corsten, Maarten
AU - Heggermont, Ward
AU - Papageorgiou, Anna-Pia
AU - Deckx, Sophie
AU - Tijsma, Aloys
AU - Verhesen, Wouter
AU - van Leeuwen, Rick
AU - Carai, Paolo
AU - Thibaut, Hendrik-Jan
AU - Custers, Kevin
AU - Summer, Georg
AU - Hazebroek, Mark
AU - Verheyen, Fons
AU - Neyts, Johan
AU - Schroen, Blanche
AU - Heymans, Stephane
PY - 2015/11/7
Y1 - 2015/11/7
N2 - 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.
AB - 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.
KW - Myocarditis
KW - Coxsackievirus B3
KW - Adverse inflammation
KW - Dilated cardiomyopathy
KW - Viral replication
U2 - 10.1093/eurheartj/ehv321
DO - 10.1093/eurheartj/ehv321
M3 - Article
C2 - 26206211
SN - 0195-668X
VL - 36
SP - 2909-U56
JO - European Heart Journal
JF - European Heart Journal
IS - 42
ER -