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Updated: Sep 27, 2025
Metabolic Characterization of Polarized M1 and M2 Bone Marrow-derived Macrophages Using Real-time Extracellular Flux Analysis
Published on: November 28, 2015
SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization
Wei Zhou1, Gaolei Hu2, Jianli He2
1State Key Laboratory of Oncogenes and Related Genes, Renji Hospital Affiliated, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Urology, Renji Hospital Affiliated, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Abstract:
The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of α-ketoglutarate (αKG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how αKG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to αKG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of αKG via glutaminolysis. We also identify glutamate dehydrogenase 1 (GLUD1) as an acetylated protein in mitochondria. The SENP1-Sirt3 axis deacetylates GLUD1 and increases its activity in glutaminolysis to promote αKG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in αKG accumulation via glutaminolysis to promote M2 polarization.
