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

Youming Chen1, Zhaoxiang Zeng2, Zetao Wei3

  • 1Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.

Molecular Biomedicine
|December 29, 2025
PubMed

Insights

The receptor for triggering expressed on myeloid cells 2 (Trem2) protects against vascular aging by regulating macrophage-vascular smooth muscle cell crosstalk. Enhancing alpha-ketoglutarate (α-KG) production via the IL-13/Trem2 axis preserves vascular function.

Area of Science:

  • Immunology
  • Vascular Biology
  • Aging Research

Background:

  • Macrophages play a critical role in vascular aging.
  • The function of Trem2 and its ligands in vascular aging remains largely undescribed.
  • Trem2 is a key immune signaling receptor expressed on myeloid cells.

Purpose of the Study:

  • To investigate the role of Trem2 in the aging vasculature.
  • To elucidate the molecular mechanisms by which Trem2 influences vascular aging.
  • To identify potential therapeutic targets for age-related vascular dysfunction.

Main Methods:

  • Transcriptome analysis, western blotting, and qPCR to assess Trem2 expression in aged mice.
  • Macrophage-specific Trem2 knockout (T2-cKO) mouse model to evaluate Trem2 deficiency effects.
  • In vivo α-KG supplementation to assess rescue effects.

Main Results:

  • Aged mice showed upregulated Trem2 in aortic senescent macrophages.
  • Macrophage-specific Trem2 knockout exacerbated arterial stiffness, impaired vascular contractility, and accelerated histological aging.
  • Trem2 deficiency intensified aortic inflammation and oxidative stress, mediated by the IL-13/Trem2/Syk-Sp1-SLC25A51 pathway and α-KG production.

Conclusions:

  • The IL-13/Trem2 axis acts as a protective mechanism against vascular aging.
  • Trem2 facilitates metabolic crosstalk between macrophages and VSMCs via α-KG-dependent pathways.
  • Trem2 represents a potential therapeutic target for vascular aging-related diseases.
Keywords:
IL-13MacrophageMetabolic reprogrammingTrem2Vascular agingα-KG

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