Mechanisms of Innate Immune Injury in Arrhythmogenic Cardiomyopathy

Abstract

ABSTRACTInhibition of nuclear factor kappa-B (NFκB) signaling prevents disease inDsg2mut/mutmice, a model of arrhythmogenic cardiomyopathy (ACM). Moreover, NFκB is activated in ACM patient-derived iPSC-cardiac myocytes under basal conditionsin vitro. Here, we used genetic approaches and sequencing studies to define the relative pathogenic roles of immune signaling in cardiac myocytes vs. inflammatory cells inDsg2mut/mutmice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias inDsg2mut/mutmice. It does this by mobilizing cells expressing C-C motif chemokine receptor-2 (CCR2+ cells) to the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction inDsg2mut/mutmice 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 ofDsg2mut/mutmice involving cardiac myocytes, fibroblasts and CCR2+ cells. Changes in gene expression in cardiac myocytes and fibroblasts inDsg2mut/mutmice were modulated by actions of CCR2+ cells. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.BRIEF SUMMARYWe have uncovered a therapeutically targetable innate immune mechanism regulating myocardial injury and cardiac function in a clinically relevant mouse model of Arrhythmogenic Cardiomyopathy (ACM).