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NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2024 Apr 02; Vol. 134 (10). Date of Electronic Publication: 2024 Apr 02. - Publication Year :
- 2024
-
Abstract
- Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) 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-Seq 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-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory 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.
- Subjects :
- Animals
Mice
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Myocytes, Cardiac immunology
Humans
Arrhythmogenic Right Ventricular Dysplasia genetics
Arrhythmogenic Right Ventricular Dysplasia metabolism
Arrhythmogenic Right Ventricular Dysplasia pathology
Myocardium pathology
Myocardium metabolism
Myocardium immunology
Macrophages metabolism
Macrophages pathology
Macrophages immunology
Receptors, CCR2 genetics
Receptors, CCR2 metabolism
Signal Transduction
Disease Models, Animal
Desmoglein 2 genetics
Desmoglein 2 metabolism
NF-kappa B metabolism
NF-kappa B genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 134
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 38564300
- Full Text :
- https://doi.org/10.1172/JCI172014