Immunometabolism in the Brain: How Metabolism Shapes Microglial Function

Immunometabolism studies uncovered critical roles for metabolism in controlling peripheral immune responses and new studies now link metabolism to microglia regulation and neuroinflammation in the brain. Microglia can rapidly adapt their energy metabolism to varying nutrient availability. The ability to switch from glycolysis to other metabolic pathways such as glutaminolysis allows microglia to maintain their essential surveillance of the brain parenchyma under acute metabolic stress. In neuroinflammatory conditions, microglia undergo metabolic reprogramming, where their main metabolic pathway shifts away from oxidative glycolysis, towards aerobic glycolysis. This metabolic reprogramming is a necessary step for proper immune actions and cytokine release in the brain. Neuroimmune responses driven by microglia, as well as brain-wide metabolic dysregulation, are emerging as two key components of neurodegenerative diseases. Studies are now pointing at defects in the microglial metabolic adaptation to disease as a critical aspect of the pathogenesis of Alzheimer’s disease. Immune cells react to their environment by flexibly reprogramming intracellular metabolic pathways that subsequently alter immune function, in a process called immunometabolism. However, in the CNS, the impact of metabolic reprogramming on microglia, neuroinflammation, and subsequently on brain function is poorly understood. As brain-resident macrophages, microglia are the CNS immune effectors and share similarities with peripheral immune cells. New tools for studying immunometabolism now allow the analysis of bioenergetic regulation with cellular resolution and, as a result, have uncovered previously unappreciated roles for microglial immunometabolism in shaping neuroinflammation. This review highlights evidence that microglia metabolism adapts to changes in brain energy homeostasis and that metabolic reprogramming regulates microglial polarization, thereby impacting pathological inflammatory responses in the brain. Immune cells react to their environment by flexibly reprogramming intracellular metabolic pathways that subsequently alter immune function, in a process called immunometabolism. However, in the CNS, the impact of metabolic reprogramming on microglia, neuroinflammation, and subsequently on brain function is poorly understood. As brain-resident macrophages, microglia are the CNS immune effectors and share similarities with peripheral immune cells. New tools for studying immunometabolism now allow the analysis of bioenergetic regulation with cellular resolution and, as a result, have uncovered previously unappreciated roles for microglial immunometabolism in shaping neuroinflammation. This review highlights evidence that microglia metabolism adapts to changes in brain energy homeostasis and that metabolic reprogramming regulates microglial polarization, thereby impacting pathological inflammatory responses in the brain. glucose analog commonly used to inhibit glycolysis. Following transport into the cell via glucose transporters, it is phosphorylated by hexokinase to generate 2-DG-6-P, which accumulates in the cell to competitively inhibit glycolysis because it cannot be metabolized further by phosphoglucose isomerase. progressive neurodegenerative disease that is the most common cause of dementia. Distinctive pathogenic features in the brain include the presence of amyloid plaques and neurofibrillary tangles. semipermeable barrier impeding the nonselective diffusion of blood-borne solutes and pathogens from entering the brain parenchymal compartment. While it mostly consists of lumen-lining endothelial cells coupled through tight junctions, astrocytic end-feet and pericytes ensheathed in the vessel wall are also involved in maintaining the integrity of the BBB. transcription factor that, upon metabolic stress, is protected from proteasome degradation. HIFs direct the transcription of genes involved in cell survival and enzymes required for metabolic adaptation to stress. a glycolipid component of gram-negative bacterial cell wall. The endotoxin is recognized by innate immune receptors and triggers immune cell activation and a strong inflammatory response. protein kinase that integrates various intracellular and extracellular signals, including nutrient and energy levels, and controls downstream activation of processes such as cellular activation, proliferation, and transcription. It is a central regulator of cellular metabolism. transmembrane receptors expressed on the surface of immune cells that bind to conserved pathogenic molecules or patterns. TLR binding results in inflammatory activation and associated cellular responses. metabolic adaptation initially observed in cancer cells by Otto Warburg, in which cells promote an increase in glucose fermentation and a relative decrease in oxidative phosphorylation capacity, even in the presence of oxygen. This anabolic glycolysis allows the conversion of nutrients into biomass, as opposed to catabolic respiration.