Fig. 2

A comprehensive summary of metabolic pathways and intermediates regulating microglia immunological function. (A) During glycolysis, glucose is converted to pyruvate, which either enters the TCA cycle via acetyl-CoA or is converted to lactate under low-oxygen conditions (anaerobic glycolysis) or in normoxic conditions (aerobic glycolysis; Warburg phenomenon). This metabolic switch promotes the expression of anti-inflammatory markers such as IL-10, TGFβ, CD206, and VEGFα. Inflammatory conditions disrupt the TCA cycle at stages involving IDH and SDH, resulting in citrate and succinate accumulation. Citrate enhances the production of prostaglandins, NO, and itaconate, whereas succinate stabilizes HIF-1α, increasing the expression of multiple glycolytic enzymes. Microglia in proinflammatory states favor fatty acid synthesis from acetyl Co-A, which leads to the secretion of additional proinflammatory cytokines. Conversely, anti-inflammatory microglia prefer β-oxidation of fatty acids, which converge into acetyl-CoA and upregulate the production of unsaturated fatty acids. (B) The receptor TREM2 on microglia enhances mTOR signaling, increasing microglial metabolic capacity, and promoting the transition to a mature disease-associated microglial profile. Amino acid sensing via mTORC1 triggers lysosomal activation, promoting proinflammatory responses. (C) Glutamine metabolism yields glutamate and α-ketoglutarate, supporting proinflammatory processes through the TCA cycle. Arginine metabolism results in the production of NO and cytokines, while its conversion to ornithine can modulate inflammation. (D) Tryptophan breakdown to kynurenine activates anti-inflammatory gene transcription through AhR binding