LAUSR

Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Infiltrating Ly6C hi blood monocytes are a key component of this healing response; however, the importance of other monocyte/macrophage populations is unclear. Here, we demonstrate in mice an essential role for splenic CD169 + Tim4 + marginal zone metallophilic macrophages (MMMs) in post-MI wound healing. CD169 + Tim4 + MMMs circulate as Ly6C low monocytes, and dynamically populate the naïve heart. After acute MI, mobilization robustly increases to the heart, where these macrophages are obligatory for apoptotic neutrophil clearance and the induction of pro-resolving and reparative tissue macrophages. Splenic MMMs are both necessary and sufficient forpost-MI wound healing, and limit late pathological remodeling.Pharmacological expansion of the splenic marginal zone during acute MI alleviates inflammation and cardiac remodeling. Finally, humans with acute MI also exhibit expansion of blood CD169 + monocytes. Hence, 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.