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Cited by 99Viral Infections and Immunology ResearchEosinophilic Disorders and SyndromesCardiac Fibrosis and Remodeling

Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy

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Diny, Nicola L., Baldeviano, G. Christian, Talor, Monica V., Barin, Jobert G., Ong, SuFey, Bedja, Djahida, Hays, Allison G., Gilotra, Nisha A. +3 more·2017·Journal of Experimental Medicine
DOI 10.1084/jem.20161702PMC PMC5379983
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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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  • The finding of eotaxin production by cardiac macrophages and fibroblasts was confirmed in endomyocardial biopsies from patients with eosinophilic myocarditis.

    “this finding was confirmed in EMB collected from patients with eosinophilic myocarditis.”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [61]

    The Patients section describes endomyocardial biopsies from patients with eosinophilic myocarditis. However, it describes using the biopsies to establish the diagnosis, not to confirm eotaxin production by macrophages or fibroblasts. The References section names a separate study on those cells as eotaxin producers, but does not establish the claimed confirmation in patient biopsies. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Following immunization, cardiac macrophages and fibroblasts primarily produce eotaxins such as CCL11 and CCL24 to recruit activated inflammatory eosinophils to the heart.

    “following immunization, cardiac macrophages and fibroblasts primarily produced eotaxins such as CCL11 and CCL24 (C-C motif chemokine ligand 24) to recruit activated inflammatory eosinophils to the heart”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [61]

    The Results section ('IL-5Tg mice develop eosinophilic myocarditis'; page unavailable) reports increased atrial Ccl11 and Ccl24 and describes eotaxins as key to eosinophil trafficking to the heart. Another Results section ('Eosinophils in the heart are activated'; page unavailable) finds that heart-infiltrating eosinophils are activated. The paper does not itself establish that macrophages and fibroblasts primarily produce those eotaxins; that point appears in the title of a different study listed in its References. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Immunization with cardiac myosin peptide induces severe eosinophilic myocarditis in mutant mice overexpressing IL-5 or lacking both IFNγ and IL-17A, but not in wild-type or control mice.

    “immunization with cardiac myosin peptide induced severe eosinophilic myocarditis in mutant mice skewing toward Th2-type responses by overexpressing IL-5 or genetically deleting both IFNγ and IL-17A but not in wild-type or control mice”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [61]

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Cited by

Sorted by citations

Authors
Diny, N. L., Baldeviano, G. C., Talor, M. V., Barin, J. G., Ong, S., Bedja, D., Hays, A. G., Gilotra, N. A., Coppens, I., Rose, N. R., & Čiháková, D.
Affiliations
Johns Hopkins University (US)
Corresponding author
Čiháková, Daniela
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2017-03-16
Volume
214
Issue
4
Pages
943-957
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20161702
PMC
PMC5379983
OpenAlex
W2597053455
Cited by
99
References
3
Citations by year
2026: 7 · 2025: 7 · 2024: 15 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 14 · 2019: 11 · 2018: 7 · 2017: 3
FWCI
7.40
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL118183, R01HL113008)
  • American Heart Association (15PRE25400010)
  • Johns Hopkins Bloomberg School of Public Health
  • American Autoimmune Related Diseases Association
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Rheumatology › Eosinophilic Disorders and Syndromes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
eosinophils, IL-4, inflammatory dilated cardiomyopathy, myocarditis, disease progression, experimental autoimmune myocarditis, IL-5, GATA-1, heart failure, eosinophilia, cardiac inflammation
MeSH terms
Animals, Autoimmune Diseases, Cardiomyopathy, Dilated, Eosinophils, Fibrosis, Humans, Interferon-gamma, Mice, Inbred BALB C, Myocarditis, Interleukin-4, Interleukin-5, Disease Progression, Interleukin-13, Interleukin-17, Mice

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