Abstract P3208: Trem2 Promotes Cardiac Repair In Myocardial Infarction Via Slc25a53 And Carbohydrate Metabolism After Improving Efferocytosis Of Macrophage

Abstract

Background: Efferocytosis and metabolic reprogramming of macrophages are necessary for myocardial infarction (MI) reparation. TREM2 is a transmembrane immune receptor that improves macrophage efferocytosis. we aim to uncover the effect of TREM2 + macrophage and explore the link between efferocytosis and metabolism in MI. Methods: Transgenic mice were used to determine the function of TREM2 in MI. Efferocytosis and metabolic functions were examined using flow cytometry, immunofluorescence. Targeted Metabolomics (LC-MS) was used to detect concentrations of metabolites. RNA-seq was used to screen the potential downstream pathways of TREM2. Protein and molecular docking were predicted with AutoDock Vina software. Result: Macrophage-specific TREM2 knockout mice (Mac-TREM2KO) showed worsened cardiac function and impaired post-MI repair. Deletion of TREM2 induced macrophages to transform into a pro-inflammatory phenotype of CCR2 + MHCII high . On the contrary, macrophages expressing TREM2 had decreased SLC25A53 transcription through the SYK-SMAD4 signaling pathway, which impaired NAD + transport into mitochondria, thereby restricting the tricarboxylic acid cycle and increasing itaconate production in anoxia condition. In vitro, itaconate secreted by TREM2 + macrophage inhibited cardiomyocyte apoptosis and increased fibroblast proliferation. Conclusion: Our data described a novel role of myeloid-derived macrophages-specific TREM2 in MI, linking efferocytosis to metabolism during cardiac repair, mainly through mitochondria SLC25A53 transporter.