NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy

• Published in: The Journal of clinical investigation 2024-04, Vol.134 (10), p.1-15
• Main Authors: Chelko, Stephen P, Penna, Vinay R, Engel, Morgan, Shiel, Emily A, Centner, Ann M, Farra, Waleed, Cannon, Elisa N, Landim-Vieira, Maicon, Schaible, Niccole, Lavine, Kory, Saffitz, Jeffrey E
• Format: Article
• Language: English
• Subjects: Age; Animals; Arrhythmogenic Right Ventricular Dysplasia - genetics; Arrhythmogenic Right Ventricular Dysplasia - metabolism; Arrhythmogenic Right Ventricular Dysplasia - pathology; Cardiac arrhythmia; Cardiac function; Cardiac muscle; Cardiomyocytes; Cardiomyopathy; CC chemokine receptors; Chemokine receptors; Chemokines; Desmoglein 2 - genetics; Desmoglein 2 - metabolism; Disease Models, Animal; Fibroblasts; Gene expression; Heart; Humans; Inflammation; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Mice; Muscle contraction; Myocardium - immunology; Myocardium - metabolism; Myocardium - pathology; Myocytes; Myocytes, Cardiac - immunology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Neutrophils; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Proteins; Receptors, CCR2 - genetics; Receptors, CCR2 - metabolism; Signal Transduction; Transcriptomes
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI172014

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.