Metabolic Reprogramming during Microglia Activation

Abstract

Microglia, the specialized macrophages of the brain, can adopt different shapes and functions, some of which may be detrimental for nervous tissue. Similar to other immune cells, the metabolic program may determine the phenotypic features of microglia, and could constitute a therapeutic target in neurological diseases. Because the knowledge on microglial metabolism was sparse we here employed mouse primary microglia cells polarized into a pro- or anti-inflammatory state to define their metabolic features. After stimulation with either IL1β/IFNγ or IL4, the activity of glycolysis, glucose oxidation, glutamine oxidation, mitochondrial and peroxisomal fatty acid β-oxidation, and fatty acid synthesis, was assessed by using radiolabeled substrates. We complemented these data with transcriptome analysis of key enzymes orchestrating these metabolic pathways. Pro-inflammatory microglia exhibit increased glucose and glutamine metabolism and suppress both fatty acid oxidation and to a lesser extent fatty acid synthesis. On the other hand, anti-inflammatory microglia display changes only in fatty acid metabolism upregulating both fatty acid oxidation and fatty acid synthesis. Importantly, also human microglia-like cells differentiated from pluripotent stem cells upregulate glycolysis in pro-inflammatory conditions. Finally, we show that glycolytic enzymes are induced in a pro-inflammatory brain environment in vivo in mice. Taken together, the distinct metabolism in pro- and anti-inflammatory microglia can constitute a target to direct the microglial phenotype.