DOI: 10.1161/circ.148.suppl_1.15358 ISSN: 0009-7322

Abstract 15358: Deletion of Csf2 Accelerates Disease Progression in a Mouse Model of Arrhythmogenic Cardiomyopathy

Stephen P Chelko, Vinay Penna, Morgan Engel, Maicon Landim-Vieira, Ann Centner, Elisa N Cannon, Kory Lavine, Jeffrey E Saffitz
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Arrhythmogenic cardiomyopathy (ACM) is a familial heart muscle disease driven by persistent innate immune signaling. We have shown that ventricular fibrosis and contractile dysfunction in Dsg2 mut/ mut mice, a model of ACM with homozygous knock-in of a variant in the gene for the desmosomal protein desmoglein-2, is mediated by activation of NFκB and actions of pro-inflammatory macrophages that express CCR2. To gain further insights into the roles of specific immune signaling pathways in the pathogenesis of ACM, we crossed Dsg2 mut/ mut mice with mice with germline deletion of Csf2 which encodes GM-CSF. This factor acts to mobilize inflammatory cells to sites of injury. Csf2 -/- mice have a normal leukocyte repertoire and no apparent phenotype under basal conditions, but show reduced immune cell infiltration after MI associated with improved healing and cardiac function. Thus, we anticipated delayed onset and less severe disease in Dsg2 mut/ mut Csf2 -/- mice compared with Dsg2 mut/ mut mice. In fact, the opposite occurred. By 8-weeks of age, Dsg2 mut/ mut Csf2 -/- mice showed a marked increase in ventricular fibrosis (18.2±6.2% of section area; n=11; p<0.05 vs all) compared to Dsg2 mut/ mut (2.6±0.4%; n=27) or wildtype (WT) control (0.9±0.1%; n=18) mice. Dsg2 mut/ mut Csf2 -/- mice also had reduced LV ejection fractions (49.6±8.3%; n=11; p<0.05 vs all) compared to Dsg2 mut/ mut (64.5±3.2%; n=27) or WT (81.8±1.0%; n=18) mice. Hearts of 8-week Dsg2 mut/ mut Csf2 -/- mice contained increased levels of pro-inflammatory chemokines (CCL21, CXCL1), matrix metalloproteinases, osteopontin (Spp1) and periostin (Postn). Single nucleus RNA sequencing studies revealed increased numbers of Spp1 + macrophages and Postn + fibroblasts, and a marked decrease in cDC2 dendritic cells in hearts of Dsg2 mut/ mut Csf2 -/- mice compared to Dsg2 mut/ mut or WT mice. cDC2 dendritic cells are known to have anti-inflammatory actions. These results suggest that cDC2 cells, mobilized by GM-CSF, may act to mitigate disease onset and severity in ACM. If so, cDC2 cells could serve as a determinant of disease expression in ACM patients.

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