SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization

The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of alpha-ketoglutarate (alpha KG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how alpha KG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to alpha KG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of alpha KG 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 alpha KG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in alpha KG accumulation via glutaminolysis to promote M2 polarization.