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Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy
Nicola L Diny1, G Christian Baldeviano2, Monica V Talor2
1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
Insights
Eosinophils are crucial for the progression of inflammatory myocarditis to dilated cardiomyopathy (DCMi). These cells drive DCMi development and severity through the production of Interleukin-4 (IL-4).
Area of Science:
- Cardiology
- Immunology
- Pathology
Background:
- Inflammatory dilated cardiomyopathy (DCMi) is a significant cause of heart failure in pediatric and young adult populations.
- The underlying mechanisms linking myocarditis to DCMi progression remain incompletely understood.
- Eosinophilia is frequently associated with the development of cardiomyopathies.
Purpose of the Study:
- To investigate the role of eosinophils in the pathogenesis of myocarditis and its progression to DCMi.
- To elucidate the specific mechanisms by which eosinophils contribute to heart failure development.
Main Methods:
- Utilized the experimental autoimmune myocarditis (EAM) mouse model.
- Employed eosinophil-deficient (ΔdblGATA1) and hypereosinophilic (IL-5Tg) mouse models.
- Assessed cardiac function using echocardiography and analyzed inflammatory markers and cytokine production (IL-4).
Main Results:
- Eosinophils were not essential for initial myocarditis induction but were required for progression to DCMi.
- Eosinophil-deficient mice were protected from developing DCMi.
- Hypereosinophilic mice developed severe DCMi, mediated by eosinophil-derived IL-4.
- IL-4-deficient mice and mice with eosinophil-specific IL-4 deletion showed protection against DCMi.
Conclusions:
- Eosinophils are critical drivers of myocarditis progression to DCMi.
- Eosinophils mediate DCMi development and severity primarily through the production of IL-4.
- Targeting eosinophils or IL-4 may offer therapeutic strategies for preventing DCMi in myocarditis patients.
Abstract:
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 ΔdblGATA1 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-5TgΔdblGATA1 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 ΔdblGATA1 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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