title: Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy.
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.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Nicola L
authors.identifier: 0000-0002-9145-5216
authors.initials: NL
authors.lastname: Diny
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: G Christian
authors.initials: GC
authors.lastname: Baldeviano
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Talor
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Jobert G
authors.initials: JG
authors.lastname: Barin
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: SuFey
authors.initials: S
authors.lastname: Ong
authors.affiliation: Department of Medicine, Division of Cardiology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Djahida
authors.identifier: 0000-0002-1685-1083
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Department of Medicine, Division of Cardiology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Allison G
authors.initials: AG
authors.lastname: Hays
authors.affiliation: Department of Medicine, Division of Cardiology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Nisha A
authors.initials: NA
authors.lastname: Gilotra
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.|Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205 dcihako1@jhmi.edu.|Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
authors.forename: Daniela
authors.identifier: 0000-0002-8713-2860
authors.initials: D
authors.lastname: Čiháková
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D018450:Disease Progression; D004804:Eosinophils / Q000502:physiology*; D005355:Fibrosis; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D018793:Interleukin-13 / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D015848:Interleukin-5 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000150:complications*
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D015848:Interleukin-5; D015847:Interleukin-4; D007371:Interferon-gamma