Splenic CD169+Tim4+ Marginal Metallophilic Macrophages Are Essential for Wound Healing 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, using a variety of in vivo murine models and orthogonal approaches, including surgical myocardial infarction, splenectomy, parabiosis, cell adoptive transfer, lineage tracing and cell tracking, RNA sequencing, and functional characterization, 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 monocytes expressing macrophage markers and help populate CD169+Tim4+CCR2-LYVE1low macrophages in the naïve heart. After acute MI, splenic MMMs augment phagocytosis, CCR3 and CCR4 expression, 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. Liver X receptor-a agonist-induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Finally, humans with acute ST-elevation MI also exhibit expansion of circulating CD169+Tim4+ cells, primarily within the intermediate (CD14+CD16+) monocyte population. 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. Naive mouse peripheral blood underwent erythrocyte lysis and leukocytes were centrifuged and collected immediately. Cells were stained with DAPI and Draq5 for 5 min. Cells were diluted to 4 mL for sorting, and viability was verified by ethidium homodimer (EtHD) staining.