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Updated: Jun 13, 2025
Systems Analysis of the Neuroinflammatory and Hemodynamic Response to Traumatic Brain Injury
Published on: May 27, 2022
Fat mass and obesity-mediated N 6 -methyladenosine modification modulates neuroinflammatory responses after traumatic
Xiangrong Chen1, Jinqing Lai1, Zhe Wu1
1Department of Neurosurgery, Second Clinical Medical College, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
Abstract:
JOURNAL/nrgr/04.03/01300535-202602000-00042/figure1/v/2025-05-05T160104Z/r/image-tiff 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 N 6 -methyladenosine is ubiquitous in the immune response of the central nervous system. The fat mass and obesity-related protein catalyzes the demethylation of N 6 -methyladenosine modifications on mRNA and is widely expressed in various tissues, participating in the regulation of multiple diseases' biological processes. However, the role of fat mass and obesity in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear. In this study, we found that the expression of fat mass and obesity was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model. After fat mass and obesity 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. Fat mass and obesity-mediated N 6 -methyladenosine demethylation accelerated the degradation of ADAM17 mRNA, while silencing of fat mass and obesity enhanced the stability of ADAM17 mRNA. Therefore, down-regulation of fat mass and obesity expression leads to the abnormally high expression of ADAM17 in microglia. These results indicate that the activation of microglia and neuroinflammatory response regulated by fat mass and obesity-related N 6 -methyladenosine modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.
Insights
Fat mass and obesity protein down-regulation in traumatic brain injury exacerbates neuroinflammation by increasing ADAM17 expression in microglia, highlighting its role in secondary injury.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglial activation drives neuroinflammation in traumatic brain injury (TBI) secondary injury.
- N6-methyladenosine (m6A) modification is crucial for central nervous system immune responses.
- Fat mass and obesity-associated protein (FTO) regulates m6A demethylation and disease processes.
Purpose of the Study:
- To investigate the role of FTO in microglial activation and neuroinflammation post-TBI.
- To elucidate the molecular mechanisms linking FTO, m6A modification, and TBI-induced neuroinflammation.
Main Methods:
- Studied FTO expression in LPS-treated BV2 cells and a TBI mouse model.
- Assessed microglial pro-inflammatory phenotype and cytokine secretion after FTO interference.
- Analyzed ADAM17 mRNA stability and degradation influenced by FTO-mediated m6A demethylation.
Main Results:
- FTO expression was significantly downregulated in both in vitro and in vivo TBI models.
- FTO interference promoted a pro-inflammatory microglial phenotype, increasing CD11b+/CD86+ cells and pro-inflammatory cytokines.
- FTO deficiency stabilized ADAM17 mRNA, leading to its overexpression in microglia.
Conclusions:
- Downregulation of FTO in microglia promotes neuroinflammation and secondary TBI injury.
- FTO-mediated m6A demethylation regulates ADAM17 mRNA stability, impacting microglial activation.
- Targeting FTO may offer a therapeutic strategy for TBI-related neuroinflammation.
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