CCL17 Protects Against Viral Myocarditis by Suppressing the Recruitment of Regulatory T Cells

BackgroundViral myocarditis is characterized by leukocyte infiltration of the heart and cardiomyocyte death. We recently identified C-C chemokine ligand (CCL) 17 as a proinflammatory effector of C-C chemokine receptor 2-positive macrophages and dendritic cells that are recruited to the heart and contribute to adverse left ventricular remodeling following myocardial infarction and pressure overload. Methods and ResultsMouse encephalomyocarditis virus was used to investigate the function of CCL17 in a viral myocarditis model. Ccl17(Gfp) reporter and knockout mice were used to identify the cell types that express CCL17 and delineate the functional importance of CCL17 in encephalomyocarditis virus clearance and myocardial inflammation. Cardiac CCL17 was expressed in C-C chemokine receptor 2-positive macrophages and dendritic cells following encephalomyocarditis virus infection. Colony-stimulating factor 2 (granulocyte-macrophage colony-stimulating factor) signaling was identified as a key regulator of CCL17 expression. Ccl17 deletion resulted in impaired encephalomyocarditis virus clearance, increased cardiomyocyte death, and higher mortality during infection early stage, and aggravated hypertrophy and fibrotic responses in infection long-term stage. An increased abundance of regulatory T cells was detected in the myocardium of injured Ccl17-deficient mice. Depletion of regulatory T cells in Ccl17-deficient mice abrogated the detrimental role of CCL17 deletion by restoring interferon signaling. ConclusionsCollectively, these findings identify CCL17 as an important mediator of the host immune response during cardiac viral infection early stage and suggest that CCL17 targeted therapies should be avoided in acute viral myocarditis.

Automated summary

This study identifies CCL17 as an important immune mediator in early-stage cardiac viral infection and suggests that CCL17 targeted therapies should be avoided in acute viral myocarditis.