Splenic CD169+Tim4+ Marginal Zone Metallophilic Macrophages Are Essential for Wound Healing and Resolution of Inflammation After Myocardial Infarction

Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6Chi blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear. Here, we establish in mice an essential role for splenic CD169+Tim4+ marginal metallophilic macrophages (MMMs) in post-MI wound healing. Splenic CD169+Tim4+ MMMs circulate in blood as Ly6Clow cells expressing express core macrophage markers and help populate CD169+Tim4+LYVE1low macrophages in the naïve heart. After acute MI, splenic MMMs augment phagocytosis and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169+Tim4+LyVE1low macrophages with an immunomodulatory and pro-resolving gene signature. These macrophages are obligatory for apoptotic neutrophil clearance, suppression of inflammation, and induction of a reparative macrophage phenotype in the infarcted heart. Splenic MMMs are both necessary and sufficient for post-MI wound healing, and limit late pathological remodeling. Pharmacological expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and cardiac remodeling. Finally, humans with acute ST-elevation MI also exhibit expansion of circulating CD169+Tim4+ macrophages. We conclude that splenic CD169+Tim4+ MMMs are required for pro-resolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.