Fat mass and obesity-mediated m6A modification modulates neuroinflammatory responses after traumatic brain injury.

The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury. The post-transcriptional modification of N6-methyladenosine (m6A) is ubiquitous in the immune response of the central nervous system. The fat mass and obesity (FTO)-related protein catalyzes the demethylation of m6A modifications on mRNA and is widely expressed in various tissues, participating in the regulation of multiple diseases' biological processes. However, the role of FTO in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear. In this study, we found that the expression of FTO was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model. After FTO interference, BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b+/CD86+ cells and the secretion of pro-inflammatory cytokines. FTO-mediated m6A demethylation accelerated the degradation of ADAM17 mRNA, while silencing of FTO enhanced the stability of ADAM17 mRNA. Therefore, down-regulation of FTO expression leads to the abnormally high expression of ADAM17 in microglia. These results indicate that the activation of microglia and neuroinflammatory response regulated by FTO-related m6A modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.