Cardiac Macrophages Promote Polarization of Macrophages toward M2 Phenotype to Improve Myocardial Remodeling via NGAL after Myocardial Infarction.

Abstract

Several studies have shown that the number of circulating neutrophils or the levels of their secreted factors, including Neutrophil Gelatinase-Associated Lipocalin (NGAL), in plasma are associated with the prognosis and mortality of patients with myocardial infarction (MI). However, the underlying mechanisms remain unclear. MI was induced in mice by permanent ligation of the left anterior descending coronary artery. Mice were then intraperitoneal administered IgG control, anti-Ly6G antibody and recombinant mouse NGAL at 1 h after the surgery and once daily from day 1-14 after surgery. At days 1, 3, 7, and 14 after surgery, echocardiogram showed that neutrophils significantly attenuates LV remodeling and reserves contractile function after MI compared with isotype control group. Flow cytometry revealed that the myocardial infiltration of macrophages decreased in MI mice with Ly6G-depleted. Moreover, WB and flow cytometry showed that macrophages differentiated by exposure to CM and NGAL, especially the latter, displayed a M2-like phenotype, expressing higher MerTK level than control M0 macrophages and the cells exposed to MPO. Meanwhile, flow cytometry indicated that the ability to remove dead cells of M2c-like macrophages triggered by NGAL significantly enhanced compared to those control M0 macrophages and the cells exposed to MPO. Most importantly, we validated that the decrease of M2c macrophage polarization in MI caused by neutrophils depletion can be reversed by NGAL in vivo. NGAL successfully induced the polarization of macrophages into M2c type. Furthermore, cardiac macrophages improve myocardial remodeling and cardiac function by inducing the polarization of M2c-like macrophages via NGAL after MI.