α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Abstract

Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

Melatonin alleviates adipose inflammation through elevating α‐ketoglutarate and diverting adipose‐derived exosomes to macrophages in mice

“…In addition, further analysis suggested that αKG inhibited inflammation response in macrophage through epigenetic reprogramming. These findings are consistent with other studies that αKG regulated the immune responses of macrophages through metabolic and epigenetic reprogramming . Our previous study had determined that melatonin inhibited inflammasome formation and pyroptosis in adipocytes .…”

“…There exists a substantial amount of evidence supporting that melatonin can accelerate key enzymes of the Kreb's cycle and the respiratory chain. Among the known metabolites, αKG has been reported to be essential for the elicitation of desirable immune responses . Recent studies also confirm that melatonin elevates cellular αKG level and prevents α‐ketoglutarate dehydrogenase activation in liver and kidney .…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…Alternately, α‐KG can be transferred to macrophages by exosomes (Figure A) . Indeed, α‐KG restricts M1 activation by intervening with the NF‐κB pathway via PHD‐mediated post‐translational modification of IKKβ (Figure A) . In LPS‐stimulated M1 macrophages, glutamine metabolism contributes to the accumulation of succinate via anaplerosis (proceeding through α‐KG) and the γ‐aminobutyric acid (GABA) shunt .…”

“…Additionally, α‐KG promotes M2 activation by Jmjd3‐dependent demethylation of H3K27 on the promoter of M2‐specific marker genes and improves oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), which are necessary for M2 macrophage polarization (Figure ) . Indeed, M2 macrophages favor α‐KG accumulation by inhibiting α‐KG dehydrogenase (α‐KGDH) activity .…”

“…Additionally, α‐KG promotes M2 activation by Jmjd3‐dependent demethylation of H3K27 on the promoter of M2‐specific marker genes and improves oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), which are necessary for M2 macrophage polarization (Figure ) . Indeed, M2 macrophages favor α‐KG accumulation by inhibiting α‐KG dehydrogenase (α‐KGDH) activity . Melatonin also improves the mitochondrial electron transport chain activity via increasing the activity of the mitochondrial OXPHOS enzymes NADH‐coenzyme Q reductase (complex I) and cytochrome c oxidase (complex IV) (Figure E) .…”