Cardiac CD206+ IL-4Rα+ macrophages expand in heart failure to drive pathological remodeling and fibrosis, and inhibition of IL-4Rα signaling in these cells alleviates left ventricular remodeling.
Inhibition of CD206+ macrophage IL-4Rα signaling alleviates adverse left ventricular remodeling and fibrosis in ischemic cardiomyopathy models.
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 (MIL-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 hi , 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 + MIL-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 MIL-4, but not IL-10-polarized (MIL-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-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. 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.
Wang et al. (Thu,) conducted a other in Ischemic cardiomyopathy and chronic heart failure. Myeloid-specific IL-4Rα deletion, macrophage adoptive transfer, and in vivo IL-4Rα gene silencing vs. Control/M[IL-10] macrophages was evaluated on Left ventricular remodeling, fibrosis, and macrophage proliferation. Cardiac CD206+ IL-4Rα+ macrophages expand in heart failure to drive pathological remodeling and fibrosis, and inhibition of IL-4Rα signaling in these cells alleviates left ventricular remodeling.