2. Academic Validation
  3. Macrophage Trem2 deficiency aggravates aging-induced vascular remodeling by acting as a non-classical receptor of interleukin-13

Macrophage Trem2 deficiency aggravates aging-induced vascular remodeling by acting as a non-classical receptor of interleukin-13

  • Mol Biomed. 2025 Dec 29;6(1):153. doi: 10.1186/s43556-025-00377-1.
Youming Chen # 1,  Zhaoxiang Zeng # 2,  Zetao Wei # 3,  Yi Zhan 4,  Luling Wu 5,  Xinlin Zhu 6 7,  Meifang Li 8 9
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
  • 2 Department of Vascular Surgery, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 201620, China.
  • 3 Department of Emergency, Dan Zhou People's Hospital, Danzhou, Hainan, 271706, China.
  • 4 Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
  • 5 Department of Endoscopy, School of Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200082, China. [email protected].
  • 6 Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, China. [email protected].
  • 7 The Center for Fungal Infectious Diseases Basic Research and Innovation of Medicine and Pharmacy, Ministry of Education, Shanghai, 200433, China. [email protected].
  • 8 Department of Emergency, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. [email protected].
  • 9 Department of Emergency, Jinjiang Municipal Hospital (Shanghai Sixth People's Hospital Fujian), Jinjiang, Fujian, 362200, China. [email protected].
  • # Contributed equally.
PMID: 41460571 DOI: 10.1186/s43556-025-00377-1
Abstract

The receptor for triggering expressed on myeloid cells 2 (Trem2), which is a key hub of immune signals, is a cell-surface receptor expressed selectively in myeloid cells. Macrophages have multi-faceted functions in vascular aging. However, the function of Trem2 and its ligands in vascular aging has not been described. Here, we investigated Trem2's function in aging vasculature using transcriptome analysis, western blotting, and quantitative polymerase chain reaction (qPCR) to assess its expression. Aged (24-month-old) wild-type mice exhibited significantly upregulated Trem2 in aortic senescent macrophages compared to young (2-month-old) controls. Compared with littermate controls, aged mice with macrophage-specific Trem2 knockout (T2-cKO) developed exacerbated arterial stiffness, impaired vascular contractility, and an acceleration of histological aging markers. Trem2 deficiency intensified aortic inflammatory responses and oxidative stress. Mechanistically, interleukin (IL)-13 from senescent macrophages directly bound Trem2, activating the Syk-Sp1-SLC25A51 pathway to enhance mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ transport. This triggered metabolic reprogramming, increasing alpha-ketoglutarate (α-KG) production, which modulated vascular smooth muscle cell (VSMC) phenotype. Notably, α-KG supplementation in vivo rescued Trem2 deficiency-driven vascular aging and dysfunction. Our study identifies the IL-13/Trem2 axis as a protective mechanism against vascular aging via α-KG-dependent metabolic crosstalk between macrophages and VSMCs. Thus, Trem2 may be a treatment target for diseases related to vascular aging.

Keywords

IL-13; Macrophage; Metabolic reprogramming; Trem2; Vascular aging; α-KG.

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