Metabolic reprogramming orchestrates immune cell differentiation and functional plasticity. The schematic illustrates the divergent metabolic programs characterizing pro-inflammatory effector cells (Left Panel) versus anti-inflammatory regulatory cells (Right Panel). (Left) Upon activation by pathogenassociated molecular patterns (e.g., LPS), Dendritic Cells (DCs) and M1 Macrophages undergo a "glycolytic switch" (Warburg effect). This process involves upregulation of the Pentose Phosphate Pathway (PPP) to generate NADPH and ATP, supporting the synthesis of pro-inflammatory cytokines (IL-1b, IL-6) and costimulatory molecules (CD80/CD86). A characteristic "truncated" TCA cycle in M1 macrophages leads to the accumulation of citrate (fueling Fatty Acid Synthesis, FAS, and NO production) and succinate. Succinate accumulation stabilizes HIF-1a, further driving glycolytic gene expression. Effector T cell subsets (Th1, Th2, Th17) similarly rely on aerobic glycolysis, glutaminolysis, and FAS, processes driven by the PI3K-Akt-mTOR-Myc signaling axis. (Right) In contrast, cells responsible for immune tolerance and resolution (M2 Macrophages, Tregs, and Memory CD8+ T cells) exhibit a metabolic preference for Oxidative Phosphorylation (OXPHOS) and Fatty Acid Oxidation (FAO). This metabolic profile is sustained by AMPK activation, which antagonizes mTOR signaling and promotes mitochondrial biogenesis via PGC-1a/b and STAT6 pathways. The PD-1/PD-L1 immune checkpoint reinforces tolerance by inhibiting glycolysis and promoting lipolysis and FAO. DC, Dendritic cell; LPS, Lipopolysaccharide; PPP, Pentose phosphate pathway; FAS, Fatty acid synthesis; FAO, Fatty acid oxidation; OXPHOS, Oxidative phosphorylation; TCA, Tricarboxylic acid cycle; HIF-1a, Hypoxiainducible factor-1a; mTOR, Mammalian target of rapamycin; AMPK, AMP-activated protein kinase; PKM2, Pyruvate kinase M2; iNOS, Inducible nitric oxide synthase; Arg1, Arginase-1; CPT1A, Carnitine palmitoyltransferase 1A; RORgt, RAR-related orphan receptor gt.
Wang et al. (Mon,) studied this question.