CD206+IL-4Rα+ Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy.

BACKGROUND: The role of cardiac CD (cluster of differentiation) 206+ macrophages in chronic heart failure (HF) is unknown. We examined whether CD206+ macrophages expressing IL (interleukin)-4Rα are key drivers of adverse left ventricular (LV) remodeling in HF.

METHODS: Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of macrophages polarized by IL-4 (M[IL-4]). Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice.

RESULTS: CD206+ macrophages steadily expanded in hearts after myocardial infarction, such that at 8 weeks after myocardial infarction, they comprised ≈85% of all macrophages. These macrophages were proliferative, predominantly CCR2- (C-C motif chemokine receptor) and MHC (major histocompatibility complex) IIhi, and correlated with LV dysfunction and fibrosis. Nearly half of CD206+ macrophages expressed IL-4Rα, and the majority of CD206+IL-4Rα+ macrophages coexpressed profibrotic FIZZ (found in inflammatory zone) 1. Bone marrow-derived CD206+ M[IL-4] macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of both cardiac mesenchymal stem cells and cardiac fibroblasts, in part related to DLL (Delta-like ligand)-4/Jagged1-Notch1 signaling in cardiac mesenchymal stem cells. Intramyocardial adoptive transfer of M[IL-4], but not IL-10-polarized (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 HF (initiated 4 weeks after myocardial infarction) in IL-4Rαf/fLysM-CreERT2 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. Last, 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.

CONCLUSIONS: 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.