TLR3 Knockdown Attenuates Pressure‐Induced Neuronal Damage In Vitro

ABSTRACT The disruption of nerve parenchyma and axonal networks triggered by spinal cord injury (SCI) can initiate a cascade of events associated with secondary injury. Toll‐like receptors play a critical role in initiating and regulating immune‐inflammatory responses following SCI; however, the precise involvement of Toll‐like receptor‐3 (TLR3) in secondary neuronal injury remains incompletely understood. To investigate the potential contribution of TLR3 in mediating neuronal pressure‐induced damage, we established a stress‐induced neuronal damage model using rat anterior horn motor neuron line (VSC4.1), which was subjected to varying levels and durations of sustained pressure. Our findings suggest that pressure induces neuronal damage and apoptosis, and reduced proliferation rates in VSC4.1 cells. Furthermore, this pressure‐induced neuronal injury is accompanied by upregulation of TLR3 expression and activation of downstream TLR3 signalling molecules. Knockdown experiments targeting TLR3 significantly alleviate pressure‐induced motor neuron injury and apoptosis within the anterior horn region while promoting mitochondria‐related autophagy and reducing mitochondrial dysfunction via the TLR3/IRF3 and TLR3/NF‐κB pathways.