Microglia and macrophage metabolism in CNS injury and disease: The role of immunometabolism in neurodegeneration and neurotrauma

Nicholas A. Devanney, Andrew N. Stewart, John C. Gensel

Research output: Contribution to journalReview articlepeer-review

162 Scopus citations


Innate immune responses, particularly activation of macrophages and microglia, are increasingly implicated in CNS disorders. It is now appreciated that the heterogeneity of functions adopted by these cells dictates neuropathophysiology. Research efforts to characterize the range of pro-inflammatory and anti-inflammatory phenotypes and functions adopted by microglia and macrophages are fueled by the potential for inflammatory cells to both exacerbate neurodegeneration and promote repair/disease resolution. The stimulation-based, M1/M2 classification system has emerged over the last decade as a common language to discuss macrophage and microglia heterogeneity across different fields. However, discontinuities between phenotypic markers and function create potential hurdles for the utility of the M1/M2 system in the development of effective immunomodulatory therapeutics for neuroinflammation. A framework to approach macrophage and microglia heterogeneity from a function-based phenotypic approach comes from rapidly emerging evidence that metabolic processes regulate immune cell activation. This concept of immunometabolism, however, is only beginning to unfold in the study of neurodegeneration and has yet to receive much focus in the context of neurotrauma. In this review, we first discuss the current views of macrophage and microglia heterogeneity and limitations of the M1/M2 classification system for neuropathological studies. We then review and discuss the current literature supporting metabolism as a regulator of microglia function in vitro. Lastly, we evaluate the evidence that metabolism regulates microglia and macrophage phenotype in vivo in models of Alzheimer's disease (AD), stroke, traumatic brain injury (TBI) and spinal cord injury (SCI).

Original languageEnglish
Article number113310
JournalExperimental Neurology
StatePublished - Jul 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors


  • Alternative activation
  • Classical activation
  • Glucose
  • Glycolysis
  • Mitochondria
  • Monocyte
  • Oxidative phosphorylation (OXPHOS)
  • Pentose phosphate pathway (PPP)
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience


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