CD206+IL-4Rα+MACROPHAGES ARE DRIVERS OF ADVERSE CARDIAC REMODELING IN ISCHEMIC CARDIOMYOPATHY
Authors: Wang Qiongxin , Ismahil Mohamed Ameen , Zhu Yujie , Rokosh Gregg , Hamid Tariq , Zhou Guihua , Pogwizd Steven M. , Prabhu Sumanth D. 
Published: October 2024

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)IIhi, 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-4Rαf/fLysM-CreERT2mice 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 vivoIL-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-, MHCIIhi, and LYVE1+, robustly proliferate with a subpopulation expressing IL-4Rα; myeloid-specific IL-4Rα deletion or IL-4Rα silencingin vivotempered CD206+macrophage proliferation and alleviated LV dysfunction, fibrosis, and remodeling.

M[IL-4] CD206+bone-marrow derived macrophages induced upregulation ofFizz1,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 ofFizz1.

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.