Neural stem cell-derived exosomal FTO protects neuron from microglial inflammatory injury by inhibiting microglia NRF2 mRNA m6A modification.

Ischemic stroke (IS) can cause neuronal cell loss and function defects. Exosomes derived from neural stem cells (NSC-Exos) improve neural plasticity and promote neural function repair following IS. However, the potential mechanism remains unclear. In this study, NSC-Exos were characterized and co-cultured with microglia. We found that NSC-Exos increased NRF2 expression in oxygen-glucose deprivation/reoxygenation and LPS-induced microglia and converted microglia from M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype. NSC-Exos reduced m6A methylation modification of nuclear factor erythroid 2-related factor 2 (NRF2) mRNA via obesity-associated gene (FTO). Furthermore, NSC-Exos reduced the damage to neurons caused by microglia's inflammatory response. Finally, the changes in microglia polarization and neuron damage caused by FTO knockdown in NSE-Exos were attenuated by NRF2 overexpression in microglia. These findings revealed that NSC-Exos promotes NRF2 expression and M2 polarization of microglial via transferring FTO, thereby resulting in neuroprotective effects.