Possible role of a dual regulator of neuroinflammation and autophagy in a simulated space environment

Abstract Radiation and microgravity exert different biological effects on the human brain during space flight. Studies rarely focus on the two combined. The central nervous system (CNS) is among the most crucial systems in the human brain. Inflammatory activation of glial cells is the principal sign of damage to nerve function. Therefore, the present study established in vitro models of radiation, simulated microgravity, and a combination of the two, in order to explore the resultant biological changes occurring in human glial cells. Experiments were performed on U-87 MG cells to study the release of inflammatory factors, changes in autophagy, and the transcription level of a key regulatory factor of histone methyltransferase enhancer of zeste 2 (EZH2). The results demonstrated that a simulated space environment significantly impacted cell growth and morphology. Neurons released cytokines that recruited monocytes, invoking an inflammatory response. Both radiation and microgravity activated cell autophagy. Finally, the meta-transcriptomics of glial cells were comprehensively analyzed, focusing on changes in the transcription of genes regulating autophagy. The results indicated that transcription levels of EZH2, the critical dual regulator of inflammation and autophagy, decreased in a simulated space environment, suggesting that U-87 MG cells inhibit EZH2 expression in such conditions. The down-regulation of EZH2 induced autophagy through activation of the mTOR pathway. Changes in levels of autophagy activated NF-κB and induced the release of the inflammatory factor IL-6. The interaction between NF-κB and EZH2 may also, in turn, affect the expression of EZH2, creating a U-87 MG cell inflammatory activation cycle. In summary, the results indicate that EZH2 may be a dual-regulator of inflammatory activation and autophagy in a simulated space environment, helping to explain the biological damage observed in the CNS in a space environment due to neuroinflammation, providing molecular targets for the health protection of astronauts during long-term space flight.