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.

How to reprogram microglia toward beneficial functions

“…Pharmacological analysis of microglia receptor/channel signaling cascades points to p‐NF‐κB, p38 ‐MAPK, iNOS, COX‐2, and NOX2 as key inflammatory intracellular pathways downregulated by agents which dampen microglia activation under pathological stimuli. Intriguingly, emerging evidence indicates that at least p‐NF‐κB, iNOS and NOX2 activity are influenced by the bioenergetics state of microglia, as clearly described in a recent review (Ghosh et al, ) (Figure ). In fact, NADPH generated via glucose metabolism through the penthose phosphate pathway (PPP) is requisite cofactor for the production of NO, by iNOS, and of superoxide, by NOX.…”

“…Inhibition of p38MAPK inflammatory pathway and PPAR‐γ activation are also in part responsible of protective effects of PUFAs and their products (Antonietta Ajmone‐Cat et al, ; De Smedt‐Peyrusse et al, ). Given the connection of NF‐κB and PPAR‐γ to the bioenergetics state of microglia (Ghosh et al, ), also dietary lipids may likely shape microglia phenotype acting on cell metabolism. In support to this hypothesis, fasting and ketogenic diet, that lead to a sustained reduction in blood glucose levels and to an increase in circulating ketones, have been reported to have anti‐inflammatory actions and suppress activation of microglia by regulating their metabolic features (Longo & Mattson, ).…”

“…Importantly, these metabolic changes were reverted by supporting ATP synthesis, suggesting that microglia dysfunctions caused by TREM-2 deficiency depend on energetic compromise (Ghosh, Castillo, Frias, & Swanson, 2017).…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Following pathological alterations, extracellular adenosine triphosphate, a source of energy metabolism, produced by dead and injured neurons can in turn activate microglia via purinergic receptors (Liu & Wang, ). Excessive activation of microglia can induce mitochondrial damage and decrease mitochondrial oxygen consumption depending on the degree of their activity, thus influencing total brain energy metabolism and exacerbating disease states (Ghosh, Castillo, Frias, & Swanson, ). Activated microglia can also be viewed as a major source of reactive oxidative stress through the release of reactive oxygen species and reactive nitrogen species, which cause oxidative damage to neurons and exacerbate the inflammatory cascade.…”

Sexually dimorphic microglia and ischemic stroke

“…The essential fuel for microglia is glucose, which they are able to take up by various glucose transporters (GLUTs) . Microglial function, in conjunction with glucose availability and glycolytic rate, is known to influence pro‐inflammatory gene expression at both the transcriptional and translational levels . All of these forms of energy consumption by microglia are important in maintaining brain homeostasis and are crucial for progression and repair of CNS injury and neurodegeneration.…”