Tricarboxylic Acid (TCA) Cycle Enzyme Alpha‐Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization

Macrophage metabolism has been increasingly studied in recent years for its potential as a therapeutic target across multiple pathologies. In this article, we propose that the tricarboxylic acid (TCA) cycle enzyme alpha‐ketoglutarate (KG) dehydrogenase (KGDH) serves as a nexus for regulating macrophage polarization toward pro‐inflammatory (M1) or anti‐inflammatory (M2) phenotypes. This is achieved through modulation of mitochondrial hydrogen peroxide (mtH 2 O 2 ) and the availability of the TCA cycle metabolites KG and succinate, which are important immunomodulatory molecules. We discuss the evidence showing KGDH is a potent source of mtH 2 O 2 in various cell types and how it could use this reactive oxygen species (ROS) to modulate signaling pathways involved in macrophage differentiation. Coupled to this, we describe emerging evidence showing that KG and succinate exert opposite signaling effects in macrophages, with the former metabolite inducing an anti‐inflammatory phenotype and the latter (succinate) promoting inflammation. This occurs through the regulation of dioxygenases involved in hypoxic signaling and epigenetic programming and the activation of G‐protein coupled receptor 91 (GPR91) by succinate. Importantly, we contend that regulating KGDH influences the availability of these two metabolites, which, along with controlling mtH 2 O 2 availability, helps control macrophage polarization. Collectively, increased mtH 2 O 2 generation and succinate are known to induce a pro‐inflammatory phenotype, whereas low mtH 2 O 2 and high KG have the opposite effect. This suggests that KGDH is a key regulator of macrophage polarization by controlling the availabilities of these immunomodulatory metabolites.