Viral myocarditis is a major cause of sudden cardiac death and can lead to dilated cardiomyopathy in adults. However, effective treatments remain elusive due to an incomplete understanding of its molecular drivers. Here, we investigate the role of β-arrestins (βarrs), scaffolding proteins that regulate GPCR signaling, in acute viral myocarditis. Using global βarr1 and βarr2 knockout (KO) mice, we assessed immune cell infiltration and apoptosis as markers of cardiac inflammation under Coxsackievirus (CVB3) infection. CVB3-infected βarr1 and 2 KO mice exhibited suppressed recruitment of NK cells, monocytes, macrophages, dendritic cells, and T cells over a broad range of viral titers at 7 days postinfection along with reduced cardiac apoptosis. At 4 days postinfection, immune cell expansion in secondary lymphoid organs, including B cells, CD8+ T cells, CD64+ myeloid progenitors, and monocyte/macrophages was also impaired in βarr KO mice. Importantly, cardiomyocyte-specific βarr1 and 2 dual deletion mirrored the attenuated inflammatory response and apoptosis observed in global βarr KO mice. Mechanistically, cardiomyocytes lacking βarr1 or βarr2 displayed defective cGAS-STING pathway activation, with impaired STING, TBK1, and IRF3 phosphorylation and inhibited IFNβ production at 24 h post-CVB3 infection. These data highlight βarrs as critical mediators of the inflammatory response in the heart and secondary lymphoid organs during viral myocarditis and demonstrate that cardiomyocyte βarrs plays a fundamental role in the inflammatory response to CVB3 viral myocarditis.Viral myocarditis can lead to dilated cardiomyopathy in adults, yet the molecular mechanisms that induce cardiac inflammation in viral myocarditis remain unclear. β-Arrestins are scaffolding proteins that mediate intracellular signaling during viral infection. We demonstrated that cardiomyocyte β-arrestins are necessary for immune cell recruitment, induction of cardiac apoptosis, and cGAS-STING pathway activation during acute coxsackievirus B3 infection. Targeting β-arrestins appears to decrease the inflammatory response in acute viral myocarditis. NEW & NOTEWORTHY
