Efferocytosis and metabolic reprogramming of macrophages play crucial roles in myocardial infarction (MI) repair. TREM2 has been proven to participate in phagocytosis and metabolism, but how it modulates myocardial infarction remains unclear. In this study, we showed that macrophage-specific TREM2 deficiency worsened cardiac function and impaired post-MI repair. Using RNA-seq, protein and molecular docking, and Targeted Metabolomics (LC–MS), our data demonstrated that macrophages expressing TREM2 exhibited decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway after efferocytosis, which impaired NAD⁺ transport into mitochondria, downregulated SLC25A53 thereby causing the breakpoint in the TCA cycle and subsequently increased itaconate production. In vitro experiments confirmed that itaconate secreted by TREM2⁺ macrophages inhibited cardiomyocyte apoptosis and promoted fibroblast proliferation. Conversely, overexpression of TREM2 in macrophages could improve cardiac function. In summary, our study reveals a novel role for macrophage-specific TREM2 in MI, connecting efferocytosis to immune metabolism during cardiac repair.

巨噬细胞的胞吞作用和代谢重编程在心肌梗死（MI）修复中发挥着至关重要的作用。TREM2已被证明参与吞噬和代谢，但其如何调节心肌梗死仍不清楚。在这项研究中，我们发现巨噬细胞特异性 TREM2 缺陷会恶化心脏功能并损害 MI 后修复。使用RNA-seq、蛋白质和分子对接以及靶向代谢组学（LC-MS），我们的数据表明，表达TREM2的巨噬细胞在胞吞作用后通过SYK-SMAD4信号通路表现出SLC25A53转录减少，这损害了NAD ⁺向线粒体的转运，下调了SLC25A53从而导致 TCA 循环的断点并随后增加衣康酸产量。体外实验证实，TREM2 ⁺巨噬细胞分泌的衣康酸可抑制心肌细胞凋亡，促进成纤维细胞增殖。相反，巨噬细胞中 TREM2 的过度表达可以改善心脏功能。总之，我们的研究揭示了巨噬细胞特异性 TREM2 在 MI 中的新作用，将胞吞作用与心脏修复过程中的免疫代谢联系起来。