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

Abstract

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. 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. 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. 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.