Macrophage Immunometabolism: Where Are We (Going)?

Metabolic reprogramming of macrophages plays a predominant role in regulating their phenotype but also their plasticity. Metabolic repurposing of mitochondria is key to the regulation of proinflammatory responses including the expression of pro-IL-1β and the generation of reactive oxygen species via reverse electron transport. In vivo macrophages are subject to a plethora of stimuli that often do not fully fit in the binary M1/M2 frame. Moreover, nutrient competition adds an extra layer of complexity to their functional regulation. The differences between human and mouse macrophages remain in the process of being elucidated. The inability of human macrophages to produce nitric oxide in vitro, unlike murine macrophages, introduces the possibility of differential metabolic reprogramming between the two cell types. A growing number of findings highlight the crucial role of metabolic reprogramming in macrophage activation. Metabolic pathways are closely interconnected and recent literature demonstrates the need for glucose metabolism in anti-inflammatory as well as inflammatory macrophages. Moreover, fatty acid oxidation (FAO) not only supports anti-inflammatory responses as described formerly but also drives inflammasome activation in inflammatory macrophages. Hence, defining glycolysis as proinflammatory and FAO as anti-inflammatory may be an oversimplification. Here we review how the rapid growth of the immunometabolism field has improved our understanding of macrophage activation and at the same time has led to an increase in the appearance of contradictory observations. To conclude we discuss current challenges in immunometabolism and present crucial areas for future research. A growing number of findings highlight the crucial role of metabolic reprogramming in macrophage activation. Metabolic pathways are closely interconnected and recent literature demonstrates the need for glucose metabolism in anti-inflammatory as well as inflammatory macrophages. Moreover, fatty acid oxidation (FAO) not only supports anti-inflammatory responses as described formerly but also drives inflammasome activation in inflammatory macrophages. Hence, defining glycolysis as proinflammatory and FAO as anti-inflammatory may be an oversimplification. Here we review how the rapid growth of the immunometabolism field has improved our understanding of macrophage activation and at the same time has led to an increase in the appearance of contradictory observations. To conclude we discuss current challenges in immunometabolism and present crucial areas for future research. central metabolite produced from citrate by ACLY. Feeds FAS and histone acetylation to support macrophage activation. both of these mitochondrial membrane-associated enzymes are essential for the import of fatty acids into mitochondria for oxidation. While CPT2 is not needed for M2 activation, the CPT1 inhibitor etomoxir can affect M2 polarization. mitochondrial conversion of fatty acids to acetyl-CoA, which enters the TCA cycle for energy production. Originally described to be required by M2 cells but also needed for inflammasome activation in M1 macrophages. production of fatty acids from acetyl-CoA through fatty acid synthase activity. Supports inflammatory signaling in M1 cells but is also needed for M2 activation. transcriptional regulator induced by hypoxia and inflammatory stimuli. Orchestrates both glycolysis and inflammatory pathways. a crucial enzyme in mouse inflammatory macrophages that generates NO for microbial killing. NO has a detrimental effect on mitochondrial complexes. antimicrobial metabolite produced by the enzyme encoded by Irg1 on citrate accumulation in M1 cells. Can inhibit SDH, causing succinate to accumulate in inflammatory macrophages. classically activated macrophages are typically activated by LPS in the presence or absence of IFNγ. These so-called M1 cells are proinflammatory and mediate host defense. Sustained M1 activation can cause chronic inflammation and tissue damage. IL-4-induced alternatively activated macrophages promote healing and mediate Th2-driven responses. major metabolic regulators that sense intracellular and extracellular signals and control macrophage metabolism and activation. generates ATP in the ETC of mitochondria; a characteristic and requirement of M2 cells. branches from glycolysis and is increased in inflammatory macrophages. Generates amino acids for protein synthesis, ribose for nucleotides, and NADPH for the production of ROS. catalyzes the last step in glycolysis and drives inflammation in diverse manners. produced from PPP-derived NAPDH by NADPH oxidase or by mitochondria through RET. Enables bacterial killing and supports HIF1α-mediated IL-1β expression. oxidizes succinate to fumarate in the TCA cycle and serves as complex II of the ETC. Crucial controller of M1 activation and its inhibition dampens inflammation. also known as the Krebs or citric acid cycle; a series of enzymatic reactions that forms a key part of the energy-generating aerobic respiration in M2 cells. The TCA cycle is broken at two places in M1 cells.