Meteorin-like regulates cardiac repair via macrophage modulation following myocardial infarction

After myocardial infarction (MI), the heart undergoes a reparative process that includes an initial acute inflammatory phase followed by a subsequent reparative phase. The transition between these phases is crucial for cardiac recovery, but the key factors remain unclear. Meteorin-like (Metrnl) promotes anti-inflammatory macrophage polarization in the myocardium, yet its role in the acute phase post-MI is unknown. We observed that macrophages infiltrating the ischemic myocardium produced elevated levels of Metrnl in both the heart and circulation 4 days post-MI. The absence of Metrnl in Metrnl⁻/⁻ mice altered myocardial healing and remodeling, with an increased presence of macrophages with a more pro-inflammatory phenotype. Conversely, cardiac Metrnl overexpression restored myocardial repair and promoted a shift toward a more anti-inflammatory macrophage phenotype. Mechanistically, Metrnl regulated macrophage-dependent production of Oncostatin M (Osm), a key cytokine in the early inflammatory phase post- MI that induces cardiomyocyte production of Reg3β. Reg3β, in turn, limits classical macrophage activation and polarization while modulating their trafficking, ultimately influencing the duration and intensity of the pro-inflammatory phase post-MI. Thus, Metrnl plays a crucial role in cardiac repair by modulating the acute phase following myocardial infarction through its regulation of macrophage populations.