The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis
The microRNA-221/-222 cluster balances the antiviral and inflammatory response in viral myocarditis
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DOI：
10.1093/eurheartj/ehv321
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发表时间：
2015-11-07
影响因子：
39.3
通讯作者：
Heymans, Stephane
中科院分区：
文献类型：
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作者：
Corsten, Maarten;Heggermont, Ward;Heymans, Stephane
目的病毒性心肌炎（viral myocarditis，VM）是健康青年心力衰竭和心源性猝死的重要原因，也是扩张型心肌病的病因学先兆。我们探讨了miR-221/-222家族的作用，上调VM。方法和结果在这里，我们表明，microRNA-221（miR-221）和miR-222水平显着升高，在急性VM引起柯萨奇病毒B3（CVB 3）。这两种miR均由不同的心肌细胞和浸润的炎性细胞表达，但它们在心肌炎时的上调主要是心肌细胞独有的。在小鼠中全身抑制miR-221/-222增加了心脏病毒载量，延长了病毒血症状态，并严重加重了心脏损伤和炎症。类似地，在体外，miR-221和miR-222的过表达抑制肠道病毒复制，而该miR簇的敲低增强病毒复制。我们鉴定并确认了许多共同协调增加的病毒复制和炎症的miR-221/-222靶标，包括ETS 1/2、IRF 2、BCL 2L 11、TOX、BMF和CXCL 1/2。体外抑制心肌细胞中的IRF 2、TOX或CXCL 12显著抑制了它们对CVB 3感染的炎症反应，证实了这些靶点在VM中的功能，并强调了miR-221/-222作为VM心脏反应调节剂的重要性。结论miR-221/-222簇协调了心脏对病毒感染的抗病毒和炎症免疫反应。它的抑制作用增加了病毒载量、炎症和VM后的整体心脏损伤。
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.