Figure 4.

The role of energy homeostasis and mitophagy in metabolic signature of M1 and M2 polarization. M1 macrophages are characterized by secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor α (TNFα). Thus, M1 macrophages display high tumoricidal and microbicidal properties. M1 macrophages rely heavily on glycolysis accompanied with increased glucose uptake and pentose phosphate pathway (PPP). Metabolic byproducts, such as reactive oxygen species (ROS) and nitric oxide (NO), are abundantly produced. During M1 macrophage polarization, succinate is released to the cytosol and promotes stabilization of hypoxia-inducible factor 1 (HIF1), which in turn drives the transcription of several genes involved in glycolysis. Translocation of both HIF1 and nuclear factor-κB (NF-κB) to the nucleus mediates the expression of numerous pro-inflammatory genes. On the other hand, anti-inflammatory function of M2 macrophages relies more on mitochondrial oxidative phosphorylation (OXPHOS), tricarboxylic cycle (TCA) fluxes, and fatty acid oxidation (FAO). AMP-activated protein kinase (AMPK) is activated and triggers FAO, which fuels OXPHOS. Mitophagy act as a key factor of M1/M2 differentiation. During M1 polarization, mitochondria clearance through mitophagy stimulation favors metabolic reprogramming to glycolysis. Activity of glycolysis, OXPHOS, TCA, and FAO is labeled with bright orange frames (less active state) and dark orange frames (more active state).