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

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.