Astrocytes are the brain's support cells, and they become "reactive" during inflammation - changing their shape, gene expression, and function. What drives these reactive states? A study in Cell Reports reveals that energy metabolism plays a key role, with the nucleoside inosine serving as a vital fuel particularly during inflammatory stress.
Inosine as Fuel
Inosine isn't typically thought of as an energy source for brain cells. But the researchers found that when astrocytes are activated by inflammatory stimuli, they increasingly rely on inosine for energy production.
The equilibrative nucleoside transporter 2 (Ent2) controls inosine flux in and out of cells. Without Ent2, astrocytes became more reactive both in culture and in living animals - their morphology and molecular profiles changed toward inflammatory states.
Energy Balance Drives Reactivity
Through metabolomics and pharmacological experiments, the researchers showed that Ent2 regulates inosine efflux and is critical for maintaining proper energy balance in astrocytes.
The key finding: when inosine fails to enter energy-producing pathways, astrocyte reactivity increases. Energy stress tips astrocytes toward inflammatory phenotypes.
Implications for Brain Inflammation
Astrocyte reactivity is relevant to many neurological conditions where inflammation plays a role. If energy metabolism drives reactive states, interventions that support astrocyte energy production might dampen harmful inflammation.
The finding adds inosine and Ent2 to the growing list of metabolic factors that regulate brain cell behavior - suggesting that the brain's "support" cells are exquisitely sensitive to their energy status.
Reference: Chang YG, et al. (2025). Equilibrative nucleoside transporter 2 modulates inosine catabolism to influence astrocyte metabolism and reactivity. Cell Reports. doi: 10.1016/j.celrep.2025.116420 | PMID: 41066233
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.