2. Academic Validation
  3. TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53

TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53

  • Cell Death Differ. 2024 Jan 5. doi: 10.1038/s41418-023-01252-8.
Shiyu Gong # 1,  Ming Zhai # 1,  Jiayun Shi # 1,  Guanye Yu # 1,  Zhijun Lei 1,  Yefei Shi 1,  Yanxi Zeng 1,  Peinan Ju 1,  Na Yang 1,  Zhuo Zhang 2,  Donghui Zhang 2 3,  Jianhui Zhuang 1,  Qing Yu 1 4,  Xumin Zhang 5,  Weixia Jian 6,  Wei Wang 7,  Wenhui Peng 8
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.
  • 2 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, 430062, China.
  • 3 Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 4 Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai, 200072, China.
  • 5 Department of Cardiology, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China.
  • 6 Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
  • 7 Pan-Vascular Research Institute of Tongji University, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai, 200072, China. wei.wang@hongene.com.
  • 8 Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China. pwenhui@tongji.edu.cn.
  • # Contributed equally.
PMID: 38182899 DOI: 10.1038/s41418-023-01252-8
Abstract

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.

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