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

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