Targeting arrhythmogenic macrophages: lessons learned from arrhythmogenic cardiomyopathy
Open accessAbstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac condition characterized by cardiac remodeling and life-threatening ventricular arrhythmias. In this issue of the JCI , Chelko, Penna, and colleagues mechanistically addressed the intricate contribution of immune-mediated injury in ACM pathogenesis. Inhibition of nuclear factor κ-B (NF-κB) and infiltration of monocyte-derived macrophages expressing C-C motif chemokine receptor-2 (CCR2) alleviated the phenotypic ACM features (i.e., fibrofatty replacement, contractile dysfunction, and ventricular arrhythmias) in desmoglein 2–mutant ( Dsg2 mut/mut ) mice. These findings pave the way for efficacious and targetable immune therapy for patients with ACM.
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NFκB activation recruits CCR2+ macrophages that release pro-inflammatory cytokines, activating cardiac fibroblasts and exacerbating myocardial injury.
“As described in Section 4.1, NFκB activation recruits CCR2+ macrophages that release pro-inflammatory cytokines, activating cardiac fibroblasts and exacerbating myocardial injury [12,103].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [103]
In “Mechanisms of immune-mediated injury in arrhythmogenic cardiomyopathy” (page unavailable), the paper links NF-κB signaling with CCR2+ macrophage recruitment and identifies CCR2+ cells as a major source of inflammatory cytokines in ACM hearts; fibroblast activation depended on those macrophages. In “Perspectives and future directions” (page unavailable), it describes cytokine-mediated effects as a likely mechanism, while saying cardiomyocyte injury and death are likely triggers of inflammation. The claim presents the entire pathway—including exacerbation of myocardial injury—as an established causal sequence more strongly than this copy does. (LLM, conf=0.84)
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Cites
Therapeutic Modulation of the Immune Response in Arrhythmogenic Cardiomyopathy
Chelko, S. P., Asimaki, A., Lowenthal, J., Bueno-Beti, C., Bedja, D., Scalco, A., Amat-Alarcon, N., Andersen, P., Judge, D. P., Tung, L., et al. (2019) · Circulation · doi:10.1161/circulationaha.119.040676 · Cited by 192 · see citing works
Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy
Chelko, S. P., Asimaki, A., Andersen, P., Bedja, D., Amat-Alarcon, N., DeMazumder, D., Jasti, R., MacRae, C. A., Leber, R., Kleber, A. G., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.85923 · Cited by 180 · see citing works
Chelko, S. P., Keceli, G., Carpi, A., Doti, N., Agrimi, J., Asimaki, A., Beti, C. B., Miyamoto, M., Amat-Codina, N., Bedja, D., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abf0891 · Cited by 92 · see citing works
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Cited by
Sorted by citations
Centner, A. M., Shiel, E. A., Farra, W., Cannon, E. N., Landim-Vieira, M., Salazar, G., & Chelko, S. P. (2024) · Nutrients · doi:10.3390/nu16132087 · Cited by 8 · see citing works
A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease
Ariyaratne, G. H. D. N., Villatore, A., Peretto, G., & Chelko, S. P. (2026) · Cells · doi:10.3390/cells15100868 · Cited by 2 · see citing works
- Authors
- Mesquita, T., & Cingolani, E.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Cingolani, Eugenio
- Venue
- Journal of Clinical Investigation
- Published
- 2024-05-15
- Volume
- 134
- Issue
- 10
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC11093592
- OpenAlex
- W4396885873
- Cited by
- 8
- References
- 4
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 1
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- American Heart Association (940033)
- Cedars-Sinai Medical Center
- National Institutes of Health (HL147570)
- National Heart, Lung, and Blood Institute (R01HL147570)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- arrhythmogenic cardiomyopathy, macrophages, monocyte-derived macrophages, CCR2, NF-κB, fibrofatty replacement, ventricular arrhythmias, cardiac remodeling, immunotherapy
- MeSH terms
- Animals, Arrhythmias, Cardiac, Humans, Macrophages, Cardiomyopathies, NF-kappa B, Arrhythmogenic Right Ventricular Dysplasia, Desmoglein 2, Mice, Receptors, CCR2
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