Macrophage Protein Trem2 Guards Aging Blood Vessels via an IL-13 Metabolic Pathway
Loss of Trem2 in macrophages accelerates vascular stiffness and dysfunction in aged mice, revealing a novel IL-13/α-KG protective axis.
Summary
Researchers discovered that Trem2, a surface receptor on macrophages, rises significantly in aged mouse aortas and acts as a protective brake against vascular aging. When Trem2 was selectively deleted in macrophages, aged mice developed worse arterial stiffness, impaired vessel constriction and relaxation, greater collagen deposition, and disrupted elastin fibers compared to controls. Mechanistically, IL-13 secreted by senescent macrophages binds directly to Trem2, activating the Syk-Sp1-SLC25A51 signaling cascade to boost mitochondrial NAD⁺ transport. This fuels alpha-ketoglutarate (α-KG) production, which in turn maintains healthy vascular smooth muscle cell (VSMC) contractile phenotype. Supplementing aged Trem2-deficient mice with α-KG rescued vascular dysfunction, confirming the pathway's therapeutic relevance.
Detailed Summary
Vascular aging drives arterial stiffness, remodeling, and ultimately cardiovascular disease, yet the cellular and molecular mechanisms remain incompletely understood. Macrophages resident in vessel walls undergo senescence with age and can either promote or limit vascular pathology depending on their activation state and signaling context. This study interrogated the role of the myeloid receptor Trem2 in this process using mouse aging models and mechanistic cell biology.
RNA sequencing of aortic tissue from 24-month-old versus 2-month-old wild-type mice identified Trem2 as one of the most upregulated genes in aged vessels, with expression confined to macrophages by flow-sorted qPCR. Immunohistochemistry confirmed elevated Trem2 protein in aged aortic sections, and a model of angiotensin II-induced vascular remodeling similarly showed increased Trem2, suggesting the receptor responds to vascular stress broadly.
To test functional significance, the team generated macrophage-specific Trem2 knockout (T2-cKO) mice and aged them to 24 months. T2-cKO mice displayed markedly elevated pulse wave velocity (PWV), indicating greater arterial stiffness. Ex vivo aortic ring assays revealed impaired phenylephrine-induced contraction and blunted relaxation to both endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) stimuli. Histologically, T2-cKO aortas showed thicker medial layers, excess collagen deposition, fragmented elastin fibers, and elevated MMP9. Contractile markers α-SMA and SM22α were downregulated while synthetic/remodeling markers (Collagen I, Collagen III, MMP-2) were upregulated, indicating VSMC phenotype switching toward a pro-fibrotic state. Transcriptome profiling and functional assays additionally showed amplified vascular inflammation and oxidative stress in T2-cKO aortas.
Mechanistically, the study's most novel finding was that IL-13, secreted by senescent macrophages, acts as a direct ligand for Trem2—a non-classical receptor for this cytokine. IL-13/Trem2 engagement activated Syk kinase, which phosphorylated and activated the transcription factor Sp1 to upregulate SLC25A51, a mitochondrial NAD⁺ transporter. Enhanced NAD⁺ availability in mitochondria reprogrammed macrophage metabolism toward elevated alpha-ketoglutarate (α-KG) production. Secreted α-KG then acted in a paracrine manner on VSMCs to maintain their contractile phenotype and limit pathological remodeling. Critically, in vivo α-KG supplementation in aged T2-cKO mice rescued arterial stiffness, vascular reactivity, and histological aging markers, validating the pathway's functional importance.
These findings position the IL-13/Trem2/α-KG axis as an endogenous vascular-protective mechanism that wanes when Trem2 is lost. The work raises the possibility that boosting Trem2 activity or supplying α-KG could represent therapeutic strategies for age-related vascular disease. However, the study was conducted exclusively in male mice, and translation to human vascular biology requires validation.
Key Findings
- Trem2 is upregulated specifically in aortic macrophages of 24-month-old aged mice versus young controls.
- Macrophage-specific Trem2 knockout worsens arterial stiffness, collagen deposition, and elastin fragmentation in aged mice.
- IL-13 from senescent macrophages directly binds Trem2, activating Syk-Sp1-SLC25A51 signaling to boost mitochondrial NAD⁺ transport.
- This signaling cascade increases α-KG production, which preserves contractile VSMC phenotype via paracrine metabolic crosstalk.
- α-KG supplementation in vivo rescues vascular dysfunction caused by Trem2 deficiency, confirming therapeutic potential.
Methodology
The study used RNA-seq of young (2-month) vs. aged (24-month) wild-type mouse aortas, macrophage-specific Trem2 conditional knockout mice aged to 24 months, and angiotensin II vascular remodeling models. Vascular function was assessed by pulse wave velocity and ex vivo aortic ring contractility; histology, immunohistochemistry, immunofluorescence, western blotting, and qPCR characterized remodeling markers; mechanistic pathway dissection employed co-immunoprecipitation, phosphoproteomics, and metabolomics with in vivo α-KG rescue experiments.
Study Limitations
The study was performed exclusively in male mice, limiting generalizability across sexes. All mechanistic work was conducted in rodent models and cell cultures, and direct human vascular validation is absent. The precise downstream mediators by which α-KG modulates VSMC phenotype in vivo require further delineation.
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