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ResearchIn-Press PreviewCardiologyImmunology Open Access | 10.1172/JCI172014
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Chelko, S. in: JCI | PubMed | Google Scholar |
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Penna, V. in: JCI | PubMed | Google Scholar
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Engel, M. in: JCI | PubMed | Google Scholar
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Shiel, E. in: JCI | PubMed | Google Scholar
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
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1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
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1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
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1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Landim-Vieira, M. in: JCI | PubMed | Google Scholar
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
Find articles by Schaible, N. in: JCI | PubMed | Google Scholar
1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
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1Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, United States of America
2Department of Medicine, Washington University in St. Louis University School of Medicine, St. Louis, United States of America
3Department of Biomedical Sciences, Florida State University College of Medicine, United States of America
4Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, United States of America
5Departments of Pathology and Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America
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Published April 2, 2024 - More info
Nuclear factor kappa-B (NFκB) is activated in arrhythmogenic cardiomyopathy (ACM) patient-derived iPSC-cardiac myocytes under basal conditions and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single cell RNA sequencing to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA sequencing and cellular indexing of transcriptomes and epitomes (CITE-seq) studies revealed marked pro-inflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells and fibroblasts in the pathogenesis of ACM.