Fascin1 exacerbates neuroinflammation and neuronal injury in acute TBI by orchestrating the AKT/mTOR, STAT3, and NF-κB signaling pathways.

BACKGROUND

Neuroinflammation drives the secondary damage following traumatic brain injury (TBI), a process largely regulated by the balance between pro-inflammatory and anti-inflammatory microglial phenotypes. Microglial activation requires rapid cytoskeletal remodeling to organize signaling complexes, yet the role of the actin-bundling protein Fascin1 in this process remains unexplored. This study investigates whether Fascin1 acts as a key upstream regulator of microglial polarization and neuroinflammatory signaling during the early stages of TBI.

METHODS

We established neuroinflammation models using controlled cortical impact (CCI) in mice and LPS-stimulated BV2 cells. Fascin1 was silenced via intracerebroventricular siRNA injection in vivo and transfection in vitro. We evaluated the effects on inflammation, neuronal survival, and key signaling pathways via qRT-PCR, Western blotting, immunofluorescence, ELISA, and behavioral assessments.

RESULTS

Fascin1 expression was significantly upregulated in both the injured cortex of TBI mice and LPS-activated microglia. Knockdown of Fascin1 effectively inhibited the pro-inflammatory state while enhancing the anti-inflammatory state, reducing cytokine secretion and attenuating neuronal apoptosis. In vivo, Fascin1 silencing significantly alleviated neurological deficits and reduced tissue loss. Mechanistically, Fascin1 depletion was associated with a concurrent dampening of the phosphorylation of critical inflammatory mediators, specifically AKT, mTOR, STAT3, and NF-κB p65.

CONCLUSIONS

Our findings demonstrate that Fascin1 promotes neuroinflammation during acute TBI. Fascin1 appears to modulate the activity of the AKT/mTOR, STAT3, and NF-κB signaling cascades, thereby shifting microglia toward a pro-inflammatory state.