Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 4, Pages 943-957Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161702
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Funding
- National Institutes of Health/National Heart, Lung, and Blood Institute [R01HL118183, R01HL113008]
- American Heart Association [15PRE25400010]
- Johns Hopkins Bloomberg School of Public Health Richard J. and Margaret Conn Himelfarb Student Support fund
- Gilead Sciences Research Scholars Program
- American Autoimmune Related Diseases Association
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Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. Patients with eosinophilia frequently develop cardiomyopathies. In this study, we used the experimental autoimmune myocarditis (EAM) model to determine the role of eosinophils in myocarditis and DCMi. Eosinophils were dispensable for myocarditis induction but were required for progression to DCMi. Eosinophil-deficient Delta dblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe ventricular and atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5, as IL-5Tg Delta d-blGATA1 mice were protected from DCMi, whereas IL-5(-/-) mice exhibited DCMi comparable with WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4-expressing cell type in the heart during EAM, IL-4(-/-) mice were protected from DCMi like.dblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4.
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