Astrocyte–neuron crosstalk through extracellular vesicle-shuttled miRNA-382-5p promotes traumatic brain injury

Abstract

Although astrocytes undergo functional changes in response to brain injury and may be the driving force of subsequent neuronal death, the underlying mechanisms remain incompletely elucidated. Here, we showed that extracellular vesicle (EV)-shuttled miRNA-382-5p may serve as a biomarker for the severity of traumatic brain injury (TBI), as the circulating EV-miRNA-382-5p level was significantly increased in both human patients and TBI model mice. Mechanistically, astrocyte-derived EVs delivered the shuttled miRNA-382-5p to mediate astrocyte–neuron communication, which promoted neuronal mitochondrial dysfunction by inhibiting the expression of optic atrophy-1 (OPA1). Consistent with these findings, genetic ablation of neuronal OPA1 exacerbated mitochondrial damage and neuronal apoptosis in response to TBI. Moreover, engineered RVG-miRNA-382-5p inhibitor-EVs, which can selectively deliver a miRNA-382-5p inhibitor to neurons, significantly attenuated mitochondrial damage and improved neurological function after TBI. Taken together, our data suggest that EV-shuttled miRNA-382-5p may be a critical mediator of astrocyte-induced neurotoxicity under pathological conditions and that targeting miRNA-382-5p-OPA1 signaling has potential for clinical translation in the treatment of traumatic brain injury. Traumatic brain injury often results in long-term disabilities. This study investigates how astrocytes contribute to nerve cell damage after TBI, focusing on extracellular vesicles and microRNAs, specifically miRNA-382-5p. The research involved blood samples from TBI patients and healthy people, and mouse experiments, to study the effects of astrocyte-derived EVs carrying miRNA-382-5p on nerve cells. The study found that after TBI, astrocytes release EVs with miRNA-382-5p, which disrupts mitochondrial function in nerve cells, causing damage. The study concludes that astrocyte-derived EVs carrying miRNA-382-5p significantly contribute to nerve cell damage after TBI. By inhibiting miRNA-382-5p, such damage can be reduced, offering a new TBI treatment approach. This research enhances our understanding of TBI and offers potential for targeted therapies. Future implications include using miRNA-382-5p as a diagnostic tool or treatment target to improve TBI outcomes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.