CD206IL-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) II, and correlated with LV dysfunction and fibrosis. Nearly half of CD206 macrophages expressed IL-4Rα, and the majority of CD206IL-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-4RαLysM-Cre mice significantly reduced CD206 macrophage proliferation and effectively depleted CD206IL-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 CD206IL-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 CD206IL-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.