Abstract
Th17 cells have been implicated in the pathogenesis of myocarditis. Interleukin (IL)-17A produced by Th17 cells is dispensable for viral myocarditis but essential for the progression to dilated cardiomyopathy (DCM). This study investigated whether the adenoviral transfer of the IL-17 receptor A reduces myocardial remodeling and dysfunction in viral myocarditis leading to DCM. In a mouse model of Coxsackievirus B3 (CVB3)-induced chronic myocarditis, the delivery of the adenovirus-containing IL-17 receptor A (Ad-IL17RA:Fc) reduced IL-17A production and decreased the number of Th17 cells in the spleen and heart, leading to the down-regulation of systemic TNF-α and IL-6 production. Cardiac function improved significantly in the Ad-IL17R:Fc- compared with the Ad-null-treated mice 3 months after the first CVB3 infection. Ad-IL17R:Fc reduced the left ventricle dilation and decreased the mortality in viral myocarditis, leading to DCM (56% in the Ad-IL17R:Fc versus 76% in the Ad-null group). The protective effects of Ad-IL17R-Fc on remodeling correlated with the attenuation of myocardial collagen deposition and the reduction of fibroblasts in CVB3-infected hearts, which was accompanied by the down-regulation of A distintegrin and metalloprotease with thrombospondin type 1 motifs (ADAMTS-1), Matrix metalloproteinase-2(MMP-2), and collagen subtypes I and III in the heart. Moreover, in cultured cardiac fibroblasts, IL-17A induced the expression of ADAMTS-1, MMP-2, and collagen subtypes I and III and increased the proliferation of fibroblasts. We determined that the delivery of IL-17-RA:Fc reduces cardiac remodeling, improves function, and decreases mortality in viral myocarditis leading to DCM, possibly by suppressing fibrosis. Therefore, the adenoviral transfer of the IL-17 receptor A may represent an alternative therapy for chronic viral myocarditis and its progression to DCM.
Highlights
Dilated cardiomyopathy (DCM) subsequent to myocarditis is a main cause of sudden death in youth and usually requires a heart transplant at the end stages of the disease [1,2]
The results confirm that the delivery of Ad-IL-17AR:Fc reduces the expression of IL-17A on day 90 post-infection in chronic Coxsackievirus B3 (CVB3) myocarditis
To confirm the inhibitory effect of AdIL-17AR:Fc, we demonstrated that the myocardial IL-17A protein was reduced significantly in Ad-IL-17AR:Fc- compared with Adnull-treated mice on day 90 post viral infection (Fig. 1C and D); Ad-IL-17AR:Fc did not alter the IL-17A receptor expression in the heart (Fig. 1E and F)
Summary
Dilated cardiomyopathy (DCM) subsequent to myocarditis is a main cause of sudden death in youth and usually requires a heart transplant at the end stages of the disease [1,2]. Th17 cells are inflammatory cells first identified by Harrington [5], and the effective IL-17 molecule acts mainly on mesenchymal cells, such as fibroblasts, and induces the expression of cytokines, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) [6]. The role these cytokines play in the onset of viral myocarditis and experimental autoimmune myocarditis is controversial [7,8]. The replication of CVB3 decreased significantly following IL-17neutralizing antibody intervention [8]
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