Metabolic regulation of immune memory and function of microglia
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
Figures
Figure 1
Cell metabolic reprogramming mediating microglia immune memory.
Microglia can be trained (red) or tolerized (blue) exhibiting enhanced or dampened inflammatory responses, respectively (Wendeln et al., 2018; Feng et al., 2020; De Sousa et al., 2021; Dong et al., 2024). Epigenetic modifications, like H3K4me1 and H3K27ac, driven by cell metabolic reprogramming, facilitate development of innate immune memory (Wendeln et al., 2018; Arts et al., 2016; Liu et al., 2017a; McManus et al., 2025; Domínguez-Andrés et al., 2019). Glycolysis is induced in trained microglia and promotes neuroinflammation (Leng et al., 2022; Lepiarz-Raba et al., 2023; Fairley et al., 2023; Wang et al., 2021; Cheng et al., 2014). TCA cycle reprogramming is key in immune training and tolerance. Succinate promotes inflammation by activating the HIF-1α–IL-1β pathway (Tannahill et al., 2013) and fumarate increases H3K4me3 marks driving trained immunity (Arts et al., 2016). On the other hand, α-ketoglutarate (αKG), produced via glutaminolysis, and itaconate promote immune tolerance (Liu et al., 2017a; McManus et al., 2025). Cholesterol synthesis is upregulated in trained macrophages and mediates trained immunity (Arts et al., 2016; Domínguez-Andrés et al., 2019; Chen et al., 2022; Bekkering et al., 2018). On the other hand, FAO and OXPHOS are generally associated with a less inflammatory and more phagocytic microglial phenotype (Leng et al., 2022; Lepiarz-Raba et al., 2023; Fairley et al., 2023). Created with BioRender.com.
Figure 2
Glucose and glutamine metabolism in microglia.
Under glucose-rich conditions (left), activated microglia exhibit enhanced glycolytic flux mediated by HK2 (Suhail et al., 2023; Fairley et al., 2023; Hu et al., 2022). Inflammatory activation triggers HK2 recruitment to mitochondria, a process regulated by TSPO, which further facilitates the glycolytic switch and inflammatory response of microglia (Fairley et al., 2023). In contrast, cytosolic HK2 promotes Aβ phagocytosis independent of its metabolic activity (Fairley et al., 2023). Lactate, the end product of glycolysis, stabilizes HIF-1α promoting a pro-inflammatory phenotype and attenuating phagocytosis (Dong et al., 2024; Zhang et al., 2023; Llibre et al., 2025; Magistretti and Allaman, 2018). Conversely, under glucose deprivation (right), microglia utilize glutamine as the main carbon source (Bernier et al., 2020a). Glutaminolysis fuels the TCA cycle with the generation of α-ketoglutarate (αKG), thereby boosting OXPHOS and enhancing ATP production (Bernier et al., 2020a; Bernier et al., 2020b). The oxidative metabolic profile is further supported by FAO and AMPK (Li et al., 2023a) and promotes a homeostatic microglial phenotype demonstrating enhanced surveillance and phagocytosis. Created with BioRender.com.
Figure 3
Lipid metabolism in microglia.
Microglia process large amounts of lipids by phagocytosing myelin or cell debris (Poitelon et al., 2020). TREM2 is required for myelin clearance, cholesterol esterification, and lipid droplet formation (Gouna et al., 2021; Nugent et al., 2020). Desmosterol, the immediate precursor of cholesterol, activates LXR signaling, promoting myelin uptake, lipid efflux, and inflammation resolution (Berghoff et al., 2021). On the other hand, inflammatory signals such as C3aR activation can induce excessive lipid accumulation due to enhanced lipid synthesis and uptake causing lysosomal rupture, oxidative stress, inflammatory activation of microglia, and reduced phagocytosis (Marschallinger et al., 2020; Planas, 2024; Arbaizar-Rovirosa et al., 2023; Gedam et al., 2023; Loppi et al., 2023). Created with BioRender.com.
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Metabolic regulation of immune memory and function of microglia
eLife 14:e107552.
https://doi.org/10.7554/eLife.107552
