Fig. 2.

Schematic view of M1 and M2 macrophage metabolism.

Left side, M1 macrophage triggers a pro-inflammatory response. The Warburg effect is activated by PI3K/AKT/mTor signaling pathway, which concomittantly activates FAS sustaining proinflammatory molecules synthesis (leucotriens and arachidonic acid). OAA sustains arginosuccinate (not figured) and arginine production, leading to NO formation by iNOS. The expression of PK in its embryonic form promotes the functioning of branched pathways on glycolysis upstream, as PPP furnishing NADPH,H⁺ for iNOS functioning (not figured). ACO2 inhibition by NO, results in a “truncated” TCA cycle: citrate is exported in the cytosol, further sustaining ACLY functioning and the production of pro-inflammatory lipids. In mitochondria, decarboxylation of aconitate in itaconate, results in succinate dehydrogenase (SDH) inhibition, a process favoring HIF-1α activation promoting glycolysis.

Right side, M2 macrophage triggers an anti-inflammatory response. AMPK inhibits PI3K/AKT: glycolysis and FAS are thus downregulated or blocked. AMPK also inhibits ACC, the first enzyme of FAS. FAO is promoted and feeds the TCA cycle, providing great amount of acetyl-coA, ATP and NADH,H⁺. PDH is blocked by NADH,H⁺ and acetyl-CoA, while pyruvate carboxylase (PC) is activated, regenerating OAA for TCA functioning. Cytosolic pyruvate (derived from glycolysis or OAA transformation) sustains PC activity. In mitochondria, OAA condensates with acetyl-coA to form citrate. High amount of citrate is produced and exported in the cytosol. Citrate sustains the production of itaconate, an anti-inflammatory molecule promoting activation of NRF2 and ATF3. Concomitantly, the break exercised by NO on ACO2 is released, allowing complete TCA functioning. The urea cycle – coupled with TCA –sustains the production of arginine, transformed by ARG1 into ornithine required for repairing (proline and polyamine synthesis).

ACLY: ATP citrate lyase, ACC: acetyl-CoA carboxylase, ACO2: aconitase 2, ARG1: arginase 1, AKT or Protein Kinase B, AKG: α-ketoglutarate, AMPK: AMP-activated protein kinase, FAO: Fatty acid β-oxidation, CAD: cis-Aconitate decarboxylase, also known as ACOD1 or Irg1, FAS: Fatty acid synthesis, F6P: fructose 6-phosphate, F1,6P: fructose-1,6-bisphosphate, GLUT: membrane glucose transporter, IDH2: isocitrate dehydrogenase 2, HIF-1α: Hypoxia-inducible factor-1α, MCT4: monocarboxylate transporter 4, NADPH,H⁺: nicotinamide adenine dinucleotide phosphate, NRF2: nuclear factor erythroid 2-related factor 2, iNOS: inducible nitric oxide synthase, NOS: nitric oxide synthase, OAA: oxaloacetate, PC: pyruvate carboxylase, PDH: pyruvate dehydrogenase, PDK1: pyruvate dehydrogenase kinase1, PFK1: phosphofructokinase1, PI3K/AKT: phosphatidylinositol 3-kinase, PKM2: pyruvate kinase embryonic form, PK; pyruvate kinase, SDH: succinate dehydrogenase, TCA: tricarboxylic acid cycle.