FOXO3-induced microRNA-128-3p promotes the progression of spinal cord injury in mice via regulating NLRP3 inflammasome-mediated pyroptosis.

Background: Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate and complex pathophysiologic mechanisms. Pyroptosis, an inflammatory form of cell death triggered by certain inflammasomes, has a key role in a variety of inflammatory diseases, including SCI. However, it is unclear whether microRNAs (miRNAs), novel regulators in the SCI, are involved in SCI-induced pyroptosis. Methods: Two GEO miRNA expression profiles (GSE158195 and GSE90452) were downloaded, and the differentially expressed miRNAs were analyzed by bioinformatics methods. An Results: Bioinformatics analysis of GSE158195 and GSE90452 datasets revealed a significant downregulation of miR-128-3p, a phenomenon that was consistently observed in the SCI mice model. Functionally, miR-128-3p upregulation improved functional behavioral recovery, relieved pathological injury, repressed oxidative stress, and alleviated pyroptosis and inflammation in the mouse SCI models. We also confirmed that Thioredoxin-interacting protein (TXNIP) was the target gene of miR-128-3p, and overexpression of TXNIP can effectively reverse the improvement of miR-128-3p in SCI cell model. Moreover, we found that transcription factor FOXO3 facilitated miR-128-3p expression, and its overexpression resulted in similar effects of miR-128-3p in the SCI cell model. Conclusion: To the best of our knowledge, this is the first report demonstrating miR-128-3p improved secondary injury in SCI through the modulation of cell pyroptosis pathway. Our results suggest that FOXO3/miR-128-3p/TXNIP/NLRP3-mediated pyroptosis axis may be a potential therapeutic target for SCI.