DTX1 Modulates Microglial M1 Polarization and Exacerbates Neuroinflammation in Traumatic Brain Injury model rats through NF - κB/IRF5

Neuroinflammation significantly contributes to the progression of traumatic brain injury (TBI), in which microglial activation playing a crucial role. This study explores the impact of Deltex E3 ubiquitin ligase 1 (DTX1) on microglial polarization and neuroinflammation post-TBI. We investigated DTX1 expression in a rat TBI model. Through gain- and loss-of-function approaches, we elucidated DTX1’s role in modulating inflammatory cytokine production and microglial polarization by reverse transcription PCR, Western blot, and enzyme-linked immunosorbent assay (ELISA). DTX1 expression was significantly up-regulated in LPS-stimulated microglia and post-TBI rat brains. Overexpression of DTX1 promoted the production of proinflammatory cytokines and induced an M1 microglial phenotype, marked by elevated inducible nitric oxide synthase (iNOS) and reduced Arginase-1 (Arg1). Conversely, DTX1 silencing exhibited anti-inflammatory effects. In the TBI rat model, DTX1 overexpression exacerbated neuroinflammation and cognitive impairments, while its knockdown ameliorated these effects. Our findings suggested that DTX1 is a key regulator of microglial polarization and neuroinflammation, herald a promising therapeutic target for TBI treatment.