M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2+ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair

Tissue-resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)-expressing macrophages have phenotypical similarities to M1-polarized macrophages, are pro-inflammatory, and recruit CCR2(+) circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2 macrophages, which phenotypically resemble M2-polarized macrophages, promote anti-inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage-derived sEV (M2(EV)) from M2-polarized bone-marrow-derived macrophages for intramyocardial injection and recapitulation of sEV-mediated anti-inflammatory activity in ischemic-reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2(EV) treatment. M2(EV) rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2(EV) inhibited CCR2(+) macrophage numbers, reduced monocyte-derived CCR2(+) macrophage recruitment to infarct sites, induced M1-to-M2 macrophage switching and promoted neovascularization. Analysis of M2(EV) microRNA content revealed abundant miR-181b-5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR-181b-5p is detrimental to beneficial M2(EV) actions and resulted in failure to inhibit CCR2(+) macrophage numbers and infarct size. Taken together, this investigation showed that M2(EV) rescued myocardial function, improved myocardial repair, and regulated CCR2(+) macrophages via miR-181b-5p-dependent mechanisms, indicating an option for cell-free therapy for AMI.