DTX1 Modulates Microglial M1 Polarization and Exacerbates Neuroinflammation in Traumatic Brain Injury Model Rats...

Microglial polarization is crucial in the pathogenesis of traumatic brain injury (TBI), yet the underlying regulatory mechanisms remain incompletely understood. In this study, we investigated the role of Deltex E3 ubiquitin ligase 1 (DTX1) in modulating microglial polarization and neuroinflammation following TBI. We established a rat TBI model and conducted both gain- and loss-of-function experiments by delivering adenoviral vectors encoding DTX1 or siRNA-DTX1-liposome complexes in vivo (into the injured rat brain) and in vitro (into cultured microglial cells). We found that that DTX1 expression was significantly upregulated in lipopolysaccharide (LPS)-stimulated microglia and in post-TBI rat brains. Overexpression of DTX1 promoted proinflammatory cytokine production and shifted microglia toward the M1 phenotype, as indicated by elevated inducible nitric oxide synthase (iNOS) and reduced arginase-1 (Arg1). Conversely, silencing DTX1 decreased iNOS and increased Arg1 expression, indicative of a shift toward the anti-inflammatory M2 phenotype. In vivo, DTX1 overexpression exacerbated neuroinflammation and cognitive deficits, whereas DTX1 knockdown mitigated these outcomes. In summary, these results identify DTX1 as a critical regulator of microglial polarization and neuroinflammation and suggest its potential as a therapeutic target for TBI.