Abstract P3066: Macrophage-derived Ccl24 Worsens Cardiac Dysfunction Following Pressure-overload

Abstract

Heart failure (HF) is the leading cause of death worldwide. Systemic inflammation is associated with HF and is considered an independent predictor of adverse cardiac outcomes. Macrophages are the most abundant immune cells in the heart and have integral roles in cardiac homeostasis and remodeling. Despite their unique identity and homeostatic functions, the precise role of cardiac macrophages during cardiac remodeling is poorly understood. We have previously reported that cardiac resident macrophages expand early in response to pressure overload injury and provide cardioprotection. Using single-cell mRNA sequencing, we revealed that these macrophages consist of distinct subsets including a population that highly expresses C-C Motif Chemokine Ligand 24 (CCL24). CCL24 is a chemokine that promotes immune cell trafficking and activation through its receptor expressed on immune cells, fibroblasts, and cardiomyocytes. Here, we tested whether CCL24 regulates cardiac adaptation to pressure overload by performing transverse aortic constriction (TAC) in whole-body CCL24 knockout (CCL24KO) mice. Aortic constriction during TAC increases the pressure overload in ventricular chambers leading to an early compensated hypertrophy and diastolic dysfunction followed by systolic dysfunction and decompensated heart failure. Despite no differences at steady state, CCL24KO mice showed an improved cardiac function after TAC-induced pressure overload. Compared with WT controls, CCL24KO mice had a higher ejection fraction and fractional shortening. Furthermore, CCL24KO mice had increased hypertrophy but improved diastolic function. These results suggest that CCL24 worsens cardiac dysfunction leading to decompensated HF in response to pressure overload. Interestingly, CCL24KO mice have higher proportions of neutrophils and eosinophils at steady state, suggesting that the presence of these cells may facilitate cardiac repair. Overall, our findings indicate that macrophage-derived CCL24 is detrimental to cardiac function in response to pressure overload injury. The results of this study uncover CCL24 as a central mechanism by which cardiac resident macrophages promote cardiac inflammation and HF.