Splenic CD169 ⁺ Tim4 ⁺ Marginal Metallophilic Macrophages Are Essential for Wound Healing After Myocardial Infarction

Abstract

BACKGROUND: Fidelity of wound healing after myocardial infarction (MI) is an important determinant of subsequent adverse cardiac remodeling and failure. Macrophages derived from infiltrating Ly6C hi (lymphocyte antigen 6 complex, locus C) blood monocytes are a key component of this healing response; however, the importance of other macrophage populations is unclear. METHODS: We used a variety of in vivo murine models and orthogonal approaches, including surgical MI, flow cytometry and single-cell RNA sequencing, lineage tracing and cell tracking, splenectomy, parabiosis, cell adoptive transfer, and functional characterization, to establish an essential role for splenic CD169 + Tim4 + (cluster of differentiation 169 + ; T cell immunoglobulin– and mucin-domain–containing molecule 4) marginal metallophilic macrophages (MMMs) in post-MI wound healing in mice. Flow cytometry was used to measure circulating CD169 + Tim4 + monocytes in humans with ST-segment–elevation MI and control participants with stable coronary artery disease undergoing elective percutaneous coronary intervention. RESULTS: Splenic CD169 + Tim4 + MMMs circulate in blood as Ly6C low monocytes expressing macrophage markers and help populate CD169 + Tim4 + CCR2 − LYVE1 low macrophages in the naive heart. After acute MI, splenic MMMs augment phagocytosis and CCR (C-C motif chemokine receptor) 3 and CCR4 expression, and robustly mobilize to the heart, resulting in marked expansion of cardiac CD169 + Tim4 + LYVE1 low macrophages with an immunomodulatory and proresolving 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-α agonist–induced expansion of the splenic marginal zone and MMMs during acute MI alleviates inflammation and improves short- and long-term cardiac remodeling. Humans with acute ST-segment–elevation MI also exhibit expansion of circulating CD169 + Tim4 + cells, primarily within the intermediate (CD14 + CD16 + ) monocyte population. CONCLUSIONS: Splenic CD169 + Tim4 + MMMs are required for proresolving and reparative responses after MI and can be manipulated for therapeutic benefit to limit long-term heart failure.