Coronin 1 deficiency protects from the development of autoimmune myocarditis by reducing CD4+ T cells.

AIMS

Dilated cardiomyopathy (DCM) caused by viral myocarditis and autoimmune processes is a frequent cause for heart failure. CD4+ T cells are indispensable for autoimmune myocarditis. Coronin 1 is required for peripheral T cell survival. We therefore hypothesized that deficiency in coronin 1 protects mice from experimental autoimmune myocarditis (EAM).

METHODS

EAM was induced in coronin 1-deficient and wild-type (WT) mice. WT CD4+ T cells isolated from spleens were transferred to coronin 1-deficient mice in a subset of animals; IL-10 was blocked in another subset before EAM induction. On day 21 mice underwent echocardiography and were sacrificed. Myocarditis severity was scored (Grades 0-4) on histology. Leukocyte fractions in blood and heart tissue were characterized. Plasma cytokines including interleukin (IL)-10 were measured and RNA sequencing of myocardial tissue was performed.

RESULTS

The severity of myocarditis was lower in coronin 1-deficient versus WT mice [median 0 (25th-75th percentile 0-2) vs. 4 (3-4), P < 0.0001]. Coronin 1-deficient animals showed significant reductions of inflammatory cells in the myocardium [median 2.5% (25th-75th percentile 1.5%-7.0%) vs. 28.3% (14.5%-54.8%), P < 0.0001]. IL-10 was selectively increased in the plasma of coronin 1-deficient mice [median 3.0 pg/mL (25th-75th percentile 1.3-5.2 pg/mL) vs. 0.4 pg/mL (0-2.0 pg/mL), P < 0.05]. Transfer of WT CD4+ T cells but not blocking of IL-10 restored EAM. Left ventricular mass was increased, but effects of myocarditis on left ventricular function were evident only on the RNA level.

CONCLUSIONS

Deficiency in coronin 1 protects from the development of EAM by reducing CD4+ T cells. This protection resulted in less structural alterations of the left ventricular myocardium. IL-10 was selectively increased in the plasma of coronin 1-deficient mice, but blocking of IL-10 was not sufficient to restore EAM.