Bioenergetic regulation of microglia

Abstract Microglia have diverse actions, ranging from synapse pruning in development to cytotoxic effects in disease. Brain energy metabolism and substrate availability vary under normal and disease states, but how these variations influence microglial function is relatively unknown. Microglia, like most other cell types, express the full complement of gene products required for both glycolytic and oxidative metabolism. Evidence suggests that microglia increase aerobic glycolysis and decrease respiration when activated by various stimuli. Mitochondrial function, glucose availability, and glycolytic rate influence pro‐inflammatory gene expression at both transcriptional and post‐translational levels. These effects are mediated through CtBP, an NADH—sensitive transcriptional co‐repressor; through effects on NLRP3 inflammasome assembly and caspase‐1 activation; through formation of advanced glycation end‐products; and by less well‐defined mechanisms. In addition to these transcriptional effects, microglial glucose metabolism is also required for superoxide production by NADPH oxidase, as glucose is the obligate substrate for regenerating NADPH in the hexose monophosphate shunt. Microglia also metabolize acetoacetate and β‐hydroxybutyrate, which are generated during fasting or ketogenic diet, and respond to these ketones as metabolic signals. β‐Hydroxybutyrate inhibits histone de‐acetylases and activates microglial GRP109A receptors. These actions suppress microglia activation after brain injury and promote neuroprotective microglia phenotypes. As our understanding of microglial activation matures, additional links between energy metabolism and microglial function are likely to be identified.