Mus musculus Transcriptome or Gene expression
The fidelity of wound healing after myocardial infarction (MI) plays a crucial role in determining subsequent cardiac remodeling and failure. Macrophages derived from Ly6Chi blood monocytes are known to be involved in this healing process, but the role of other macrophage populations remains unclear. This study identifies the essential role of splenic CD169+Tim4+ marginal metallophilic macrophages (MMMs) in post-MI wound healing using various in vivo murine models and advanced techniques. These splenic MMMs circulate as Ly6Clow monocytes in blood, express macrophage markers, and contribute to populating CD169+Tim4+CCR2-LYVE1low macrophages in the naive heart. After acute MI, splenic MMMs enhance phagocytosis, express CCR3 and CCR4, and significantly mobilize to the heart. This results in a marked expansion of cardiac CD169+Tim4+LyVE1low macrophages with an immunomodulatory and pro-resolving gene signature. These macrophages are critical for clearing apoptotic neutrophils, suppressing inflammation, and promoting a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing and help limit late-stage pathological remodeling. Treatment with a liver X receptor-a agonist, which expands the splenic marginal zone and MMMs during acute MI, reduces inflammation and improves short- and long-term cardiac remodeling. Additionally, humans with acute ST-elevation MI also show an expansion of circulating CD169+Tim4+ cells, particularly within the intermediate (CD14+CD16+) monocyte population. In conclusion, splenic CD169+Tim4+ MMMs are essential for the pro-resolving and reparative responses after MI and can be targeted for therapeutic strategies to limit long-term heart failure.