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

Abstract

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.