Pro- and Anti-Inflammatory Macrophages Adjust UCP2 Protein Levels Based on Their Intrinsic Metabolism and Available Metabolites

The immune and metabolic responses of macrophages are closely linked. Mitochondrial uncoupling protein 2 (UCP2), proposed to facilitate metabolite transport, is involved in regulating inflammation and glucose metabolism in macrophages. However, its significance and regulatory mechanism in subsets of macrophages with distinct metabolic profiles remain unclear. In this study, we demonstrate that under physiological nutrient conditions, inflammatory stimuli in classically activated macrophages (via LPS) reduce UCP2 expression in line with decreased oxygen consumption rates, indicating mitochondrial suppression. In contrast, alternatively activated macrophages (via IL4) displayed higher UCP2 levels and enhanced respiration. Under glucose deprivation, LPS-stimulated macrophages retained mitochondrial activity despite lower UCP2 levels. Blocking pyruvate entry into the mitochondria reduced UCP2 expression, highlighting the connection between glycolysis and mitochondrial metabolism. Mimicking the hypoxic milieu characteristic of LPS-activated macrophages through CoCl 2 treatment of IL-4-activated macrophages resulted in decreased UCP2 expression, suggesting that hypoxia broadly mediates UCP2 suppression in macrophages. Overall, our findings suggest that UCP2 protein levels are modulated by metabolic alterations in macrophages, with pyruvate acting as a key regulator of UCP2 abundance. This emphasizes the importance of UCP2 in linking glycolysis with mitochondrial metabolism, providing insights for developing therapeutic strategies for diseases involving immunometabolic dysregulation.