Targeting immunometabolism during cardiorenal injury: roles of conventional and alternative macrophage metabolic fuels

Figures

• 

  FIGURE 1. Shifts in whole tissue and macrophage metabolic shifts during cardiorenal injury. The healthy heart primarily relies on fatty acid oxidation, followed by glucose oxidation, with minor contributions from lactate and ketone oxidation. The kidney primarily relies on glucose oxidation, followed by fatty acid oxidation (mainly in the proximal tubule), with minor contributions from lactate and ketone oxidation. During cardiac injury, ketone oxidation and glycolysis are increased, while mitochondrial dysfunction results in impaired fatty acid and glucose oxidation. Macrophages within these tissues also shift their metabolic status. Resident macrophages rely on fatty acid and glucose oxidation, while monocytes and M1 macrophages primarily rely on glycolysis. M2 macrophages also primarily rely on glucose and fatty acid oxidation. Red text indicates unknown pathways. PT—proximal tubule.

• 

  FIGURE 2. Mechanisms by which alternative fuels promote M2 polarization. BHB and AA (ketones), and lactate, are taken up by MCT1 in the plasma membrane, then oxidized in the mitochondrial TCA cycle. Increased TCA cycle activity increases levels of alpha-KG, which blocks NLRP3 inflammasome activation. Full TCA cycle activation also prevents accumulation of succinate, decreasing its activation of HIF-1α and its activation of M1 genes. Extracellular lactate and BHB can also bind to membrane G-protein coupled receptors, which activate intracellular signaling pathways that block inflammasome activation. Lactate can also be used to covalently modify histone proteins (lactylation), leading to activation of M2 genes. α-KG—alpha-ketoglutarate; AA—acetoacetate; BHB—beta-hydroxybutyrate; Gpr—G-protein receptor; HCA2—hydroxycarboxylic acid receptor 2; HIF-1α—hypoxia-inducible factor 1-alpha; MCT1—monocarboxylate transporter 1; SCOT—succinyl-CoA:3-ketoacid-coenzyme A transferase; TCA—tricarboxylic acid.