Deletion of JDP2 improves neurological outcomes of traumatic brain injury (TBI) in mice: Inactivation of Caspase-3.

Traumatic brain injury (TBI) is a major cause of death and disability, also resulting in long-term serious neurological impairment in survivors. However, the pathogenesis of TBI has not been fully understood. Jun dimerization protein 2 (JDP2) is a member of the AP-1 family of transcription factors, containing a basic region-leucine zipper motif. JDP2 plays essential roles in various cellular processes, including differentiation, apoptosis, senescence and aging. In the study, we attempted to explore the effects of JDP2 on TBI progression both in vivo and in vitro. The wild type (WT) and JDP2 knockout (KO) mice were employed in our study and were subjected to TBI. The results showed that JDP2-deficient mice exhibited improved cognitive functions in TBI mice. The inflammatory cytokines, glial amount and apoptosis, as well as the protein of cleaved Caspase-3 were significantly increased after TBI in WT mice, and all these up-regulation were significantly mitigated by JDP2 knockout in mice. We also found that TBI induced JDP2 expression in hippocampus of mice. Lipopolysaccharide (LPS) also stimulated JDP2 expression levels in astrocytes isolated from WT mice, indicating the critical role of JDP2 in TBI. Suppressing Caspase-3 activation could reduce LPS-induced inflammation in astrocytes. Consistent with the results in vivo, LPS-induced inflammatory response and apoptosis were reversed by JDP2 deficiency in cells. Notably, we found that over-expressing JDP2 could further promoted inflammation, apoptosis and Caspase-3 activation induced by LPS. Collectively, JDP2 knockout effectively attenuate TBI in vivo and in vitro through blocking Caspase-3 activation, providing a potential therapeutic target for TBI or even other neurological disorders.