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 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. [Display omitted] •IL-4 activates SENP1-Sirt3 axis to augment M2 macrophage polarization•SENP1-Sirt3 axis controls αKG accumulation via glutaminolysis in M2 polarization•SENP1-Sirt3 axis deacetylates and activates GLUD1 in glutaminolysis Zhou et al. find that IL-4 activates SENP1-Sirt3 signaling in mitochondria to deacetylate glutamate dehydrogenase 1 (GLUD1) to promote glutaminolysis and α-ketoglutarate (αKG) production leading to macrophage M2 polarization.