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.

Keywords: heart failure; inflammation; macrophages; myocardial infarction; spleen.