Astrocyte-derived Exosomal lncRNA 4933431K23Rik Modulate Microglial Phenotype and Improve Post-traumatic Recovery via SMAD7 Regulation.

Astrocyte-microglial interaction plays a crucial role in brain injury-associated neuroinflammation. Our previous data illustrated that astrocytes secrete microRNA, leading to anti-inflammatory effects on microglia. Long non-codingRNAs participate in neuroinflammation regulation post traumatic brain injury. However, the effect of astrocytes on microglial phenotype via long non-codingRNAs and the underlying molecular mechanisms remain elusive. We used long non-codingRNA sequencing on murine astrocytes and found that exosomal long non-codingRNA 4933431K23Rik attenuated traumatic brain injury-induced microglial activation in vitro and in vivo and ameliorated cognitive function deficiency. Furthermore, microRNA and messengerRNA sequencing together with binding prediction illustrated that exosomal long non-codingRNA 4933431K23Rik up-regulates E2F7 and TFAP2C expression by sponging miR-10a-5p. Additionally, E2F7 and TFAP2C, as transcription factors, regulated microglial Smad7 expression. Using Cx3cr1-Smad7 overexpression of adeno-associated virus, microglia specifically overexpressed Smad7 in the attenuation of neuroinflammation, resulting in less cognitive deficiency post traumatic brain injury. Mechanically, overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, preventing NF-κB signaling activation. The Smad7 activator asiaticoside alleviates neuroinflammation and protects neuronal function in traumatic brain injury mice. This study revealed that an exosomal long non-codingRNA from astrocytes attenuates microglial activation post traumatic brain injury by up-regulating Smad7, providing a potential therapeutic target.