Metabolic Reprogramming in Neuroinflammatory Responses

Metabolic reprogramming in neuroinflammation refers to dynamic shifts in cellular energy pathways that underpin the activation, function and fate of central nervous system immune cells, principally microglia and astrocytes. In homeostasis, these cells rely predominantly on oxidative phosphorylation (OXPHOS) for efficient ATP generation. Upon exposure to inflammatory stimuli, however, there is a rapid switch towards aerobic glycolysis, mirroring the Warburg effect described in cancer. This allows faster ATP production and provision of biosynthetic intermediates required for cytokine synthesis and phagocytic activity. Concurrently, alternative substrates such as glutamine can sustain mitochondrial function under glucose‐deprived conditions, ensuring continued immune surveillance. Lipid metabolism, amino acid catabolism and autophagic flux are all remodelled to support the energetic and biosynthetic demands of a neuroinflammatory milieu. Such adaptations influence phenotypic polarisation, with distinct metabolic programmes associated with pro‐inflammatory (M1‐like) or reparative (M2‐like) states. Dysregulated metabolic reprogramming contributes to chronic neurodegeneration by perpetuating inflammatory cycles, impairing debris clearance and altering redox balance. Understanding these pathways offers avenues for therapeutic intervention in diseases such as Alzheimer’s, Parkinson’s and multiple sclerosis, where modulating cellular metabolism may restore homeostasis and limit neuronal damage.

Research from Nature Portfolio

Recent studies have elucidated the remarkable metabolic flexibility of microglia in vivo, demonstrating that, under conditions of hypoglycaemia or glucose deprivation, these cells switch from glycolysis to glutaminolysis to power mitochondrial respiration. This substrate switch is orchestrated by mTOR‐dependent signalling and preserves microglial process motility, damage sensing and phagocytic functions even when primary energy sources are scarce. The work highlights key regulatory nodes that maintain surveillance roles of microglia, emphasising how nutrient availability directly shapes immune competence in the brain.

Metabolic Reprogramming in Neuroinflammatory Responses publication trend

The graph below shows the total number of articles in metabolic reprogramming in neuroinflammatory responses across all publications each year (not limited to Nature Index journals).

Technical terms

Oxidative phosphorylation (OXPHOS): Mitochondrial process generating ATP through electron transport and proton gradient formation.

Glycolysis: Cytosolic conversion of glucose to pyruvate, yielding ATP rapidly and providing intermediates for biosynthesis.

Glutaminolysis: Catabolism of glutamine to feed the tricarboxylic acid cycle, supporting energy production under glucose limitation.

mTOR signalling: Nutrient‐sensing kinase pathway that regulates metabolism, growth and autophagy in response to cellular energy status.

Microglial polarisation: Functional phenotypes of microglia, ranging from pro‐inflammatory (M1‐like) to anti‐inflammatory or reparative (M2‐like), linked to distinct metabolic profiles.

References

1. Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2. Advanced Science (2024).
2. Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics. Translational Neurodegeneration (2023).
3. Microglial metabolic flexibility supports immune surveillance of the brain parenchyma. Nature Communications (2020).
4. Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response. Frontiers in Immunology (2020).
5. Early glycolytic reprogramming controls microglial inflammatory activation. Journal of Neuroinflammation (2021).