PU.1 Inhibition Attenuates Neuroinflammation and Pyroptosis After Traumatic Brain Injury by Modulating Microglial...

The exact role of transcription factor PU.1 in traumatic brain injury (TBI) remains unclear. This study aims to investigate the role of PU.1 in microglial function and neuroinflammation following TBI.

A combination of bioinformatic analysis of public sequencing data sets (GSE269748 and GSE128543), a mouse TBI model (controlled cortical impact), and in vitro experiments using LPS-stimulated BV2 microglial cells was used. The specific PU.1 inhibitor DB2313 was administered to assess its effects. RNA sequencing, reverse transcription-polymerase chain reaction (RT-PCR), Western blot, immunofluorescence staining, scratch wound assay, and phagocytic capacity assay were used.

PU.1 was significantly up-regulated in the sites of injured cortex post-TBI and LPS-treated microglia. Its inhibition by DB2313 attenuated microglial polarization towards the proinflammatory M1 phenotype, reduced the expression of inflammatory mediators, and suppressed microglial migration while enhancing phagocytosis. Mechanistically, PU.1 exacerbated neuroinflammation via the TLR4/MyD88/NF-κB signaling pathway and promoted NLRP3 inflammasome-Caspase-1-mediated pyroptosis.

PU.1 is a key regulator of neuroinflammation and pyroptosis after TBI. Targeting PU.1 represents a promising therapeutic strategy to mitigate microglial-mediated inflammatory damage and improve outcomes following TBI.