CD206+IL-4Rα+MACROPHAGES ARE DRIVERS OF ADVERSE CARDIAC REMODELING IN ISCHEMIC CARDIOMYOPATHY

ABSTRACT BACKGROUND Cardiac CD206 + macrophages expand acutely after myocardial infarction (MI) to promote wound healing; however, their role in chronic heart failure (HF) is unknown. We tested the hypothesis that cardiac CD206 + macrophages expressing interleukin(IL)-4Rα are key drivers of adverse left ventricular (LV) remodeling in HF. METHODS AND RESULTS Adult male C57BL/6 mice underwent non-reperfused MI to induce HF, or sham operation, and cardiac macrophages were profiled using flow cytometry. As compared to sham, CD206 + macrophages steadily expanded in post-MI hearts during LV remodeling, such that at 8 w post-MI they comprised ∼85% of all macrophages. These macrophages were robustly proliferative and predominantly C-C motif chemokine receptor (CCR2) - and major histocompatibility complex (MHC)II hi , with >90% of CD206 + CCR2 - macrophages expressing the resident macrophage marker LYVE-1. CD206 + macrophage abundance correlated with LV dysfunction and fibrosis. Nearly half of CD206 + macrophages expressed IL-4Rα, and the majority of CD206 + IL-4Rα + macrophages co-expressed the pro-fibrotic protein found in inflammatory zone (FIZZ)1. IL-4-polarized bone marrow derived CD206 + macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of cardiac mesenchymal stem cells (cMSCs), in part related to DLL-4/Jagged1-Notch1 signaling. Intramyocardial adoptive transfer of M[IL-4], but not M[IL-10], CD206 + macrophages to naïve mice, induced progressive LV remodeling over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, and apoptosis. Myeloid-specific IL-4Rα gene deletion in established HF (initiated 4 w post-MI) in IL-4Rα f/f LysM-Cre ERT2 mice significantly reduced CD206 + macrophage proliferation and effectively depleted CD206 + IL-4Rα + cardiac macrophages. This was associated with abrogation of LV remodeling progression, reduction of cardiac fibrosis, and improved neovascularization. In vivo IL-4Rα gene silencing in mice with established HF effectively depleted cardiac CD206 + IL-4Rα + macrophages and reversed LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressed both local and systemic inflammation. Lastly, alternatively activated CD206 + and CD163 + macrophages were significantly expanded in human failing hearts and correlated with fibrosis. The majority of CD163 + macrophages expressed IL-4Rα and FIZZ3, the human homolog of FIZZ1. CONCLUSION Cardiac CD206 + IL-4Rα + macrophages proliferate and expand in HF and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206 + macrophage IL-4Rα signaling alleviates LV remodeling in ischemic cardiomyopathy. CLINICAL PERSPECTIVE What is new? In the failing heart after myocardial infarction (MI), CD206 + macrophages, primarily CCR2 - , MHCII hi , and LYVE1 + , robustly proliferate with a subpopulation expressing IL-4Rα; myeloid-specific IL-4Rα deletion or IL-4Rα silencing in vivo tempered CD206 + macrophage proliferation and alleviated LV dysfunction, fibrosis, and remodeling. M[IL-4] CD206 + bone-marrow derived macrophages induced upregulation of Fizz1, and FIZZ1-dependent cardiac mesenchymal myofibroblast differentiation; intramyocardial adoptive transfer of M[IL-4] macrophages induced cardiac remodeling and fibrosis. Humans exhibit expansion of alternatively activated macrophages in the failing heart marked by CD206 and CD163 expression, with predominance of a subpopulation expressing IL-4Rα and Fizz3, the human homolog of Fizz1 . What are the clinical implications? An expanded pool of alternatively activated CD206 + IL-4Rα + cardiac macrophages are key drivers of LV remodeling in heart failure, inducing an immuno-fibrotic and para-inflammatory response in part dependent on FIZZ1. Targeting IL-4 signaling in CD206 + macrophages represents a potential therapeutic approach to limit long-term cardiac remodeling in heart failure.