Eosinophilic myocarditis is a rare form of myocarditis with a poorly understood pathogenesis and an exceptionally poor prognosis. Patients with eosinophilic myocarditis present with a rapid, acute onset, and commonly progress to heart failure. We have developed several models of eosinophilic experimental autoimmune myocarditis (Eo-EAM) using either IL5CD2 transgenic mice or mice deficient in both IFN? and IL17A (IFN?-/-IL17A-/-) and immunizing them with myocarditogenic peptide in CFA. Both strains of mice develop severe myocarditis with more than 30% of their heart infiltrate comprised by eosinophils. Based on these observations, we propose the overarching hypothesis that Th2-driven inflammation, especially eosinophilic infiltration, contributes significantly to the most severe forms of immune-mediated heart disease. We propose to investigate the mechanisms underlying the pathogenesis of eosinophilic myocarditis by identifying the most critical cells and mediators that could be targets for a potential treatment. First, in Aim 1, we will examine the induction of eosinophilic autoimmune responses at the level of innate immunity. We hypothesize that early production of IL4 and IL13 by cells activated during the innate immune response leads to autoaggressive Th2 differentiation in the pathogenesis of eosinophilic EAM. We will employ transfer experiments to determine the ability of dendritic cells (Subaim 1.1), basophils (Subaim 1.2), and nuocytes (Subaim 1.3) to induce Eo-EAM. Additionally, we will use in vivo depletions to establish the necessity of these cells in the potentiation of Eo-EAM.
In Aim 2, we will study determinants of eosinophil trafficking to the heart and the effectiveness of blocking such pathways to prevent eosinophilic myocarditis. Using IL5-/- mice, we have established that the recruitment of eosinophils to the heart during myocarditis is IL5-independent. In this Aim, we will investigate whether the CCR3 (Subaim 2.1) or eicosanoid lipid derivative pathways (Subaim 2.2) contribute to trafficking of eosinophils to the heart.
In Aim 3, T cell decision-making in the pathogenesis of eosinophilic myocarditis will be examined. First, we will determine if IFN? and IL17A control development of eosinophilic myocarditis through Th2 responses (Subaim 3.1). To farther examine the sufficiency and necessity of Th2 differentiation for Eo-EAM development, we will employ IL4R?F709 mice, which carry a point mutation in the IL4 receptor essentially rendering the signaling pathway hyperactive (Subaim 3.2).
In Aim 4, we will explore possible therapeutic effects of blockade of one of the major products that eosinophils release upon activation, eosinophil peroxidase (EPO). Dissecting the mechanisms by which different cell types and cell mediators drive eosinophilic myocarditis development can lead to greater understanding of the pathogenesis of eosinophilic myocarditis and suggest ways in which this life-threatening disease can be prevented or treated.

Public Health Relevance

Eosinophilic myocarditis is a rare form of myocarditis with a poorly understood pathogenesis and an exceptionally poor prognosis. By analyzing the critical pathways responsible for this disease we will seek opportunities to improve treatment of this and other eosinophilic inflammatory disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Kaltman, Jonathan R
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Johns Hopkins University
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Diny, Nicola L; Hou, Xuezhou; Barin, Jobert G et al. (2016) Macrophages and cardiac fibroblasts are the main producers of eotaxins and regulate eosinophil trafficking to the heart. Eur J Immunol 46:2749-2760
Barin, Jobert G; Talor, Monica V; Schaub, Julie A et al. (2016) Collaborative Interferon-γ and Interleukin-17 Signaling Protects the Oral Mucosa from Staphylococcus aureus. Am J Pathol 186:2337-52
Wu, Lei; Diny, Nicola L; Ong, SuFey et al. (2016) Pathogenic IL-23 signaling is required to initiate GM-CSF-driven autoimmune myocarditis in mice. Eur J Immunol 46:582-92
Rose, Noel R (2016) Viral myocarditis. Curr Opin Rheumatol 28:383-9
Ong, SuFey; Ligons, Davinna L; Barin, Jobert G et al. (2015) Natural killer cells limit cardiac inflammation and fibrosis by halting eosinophil infiltration. Am J Pathol 185:847-61
Fontes, Jillian A; Rose, Noel R; Čiháková, Daniela (2015) The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine 74:62-8
Rose, Noel R (2015) Molecular mimicry and clonal deletion: A fresh look. J Theor Biol 375:71-6
Wu, Lei; Ong, SuFey; Talor, Monica V et al. (2014) Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med 211:1449-64
Rose, Noel R (2014) Learning from myocarditis: mimicry, chaos and black holes. F1000Prime Rep 6:25
Barin, Jobert G; Baldeviano, G Christian; Talor, Monica V et al. (2013) Fatal eosinophilic myocarditis develops in the absence of IFN-γ and IL-17A. J Immunol 191:4038-47

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