Toll-like Receptor-4 (TLR4) as a Potential Target for Minimizing the Long-term Cognitive and Behavioral Sequelae of Traumatic Brain Injury (TBI)
Jose C Alonso-Escalante, Diala F Hamade, William Fulton, Chhinder Sodhi, David J Hackam, *Isam W Nasr
Johns Hopkins University, Baltimore, MD
Background: TLR4 signaling has been implicated in microglial activation, which initiates the neuroinflammatory cascade following traumatic brain injury (TBI). We sought to investigate whether the absence of TLR4 signaling would mitigate the neurobehavioral changes observed following TBI, in a murine model.
Methods: A controlled cortical impact model using wild-type (WT) and TLR4-knockout (KO) mice was performed (4-8 week-old males). Contusion volume was measured using MRI. Flow cytometry was used to quantify M1-like (CD86+) and M2-like (CD206+) microglial populations. Neurobehavior (Y-maze,Open Field) was assessed on post-injury day (PID) 7&28. All other analyses were performed on PID 1,7,35. T-test and two-way ANOVA were used for statistical analysis.
Findings: The volume of brain injury in TLR4-KO mice was greater (19±2mm3,n=3) when compared to WT mice (11±1mm3,n=4) on PID1(p=0.01). This was associated with worse cognitive performance and hyperactivity in the TLR4-KO group on PID7. However, TLR4-KO mice had a smaller lesion (4±1mm3,n=5) than WT mice (8±1mm3,n=5) on PID7 (p=0.003). Interestingly, WT mice still outperformed TLR4-KO mice in cognitive tasks, and displayed less motor activity on PID28. FACS-analysis demonstrated greater M1-like microglial polarization in the TLR4-KO group than in the WT group on PID1(TLR4-KO=22.23±0.90%,n=3;WT=14.35±2.10,n=4,p=0.05).
Conclusions: Lack of TLR4-signaling results in worse cognitive performance and anxiety-like behavior up to 28 days post-trauma. Up-regulation of pro-inflammatory M1-like microglia exacerbates brain damage in the first day. This has a sustained negative impact on cognition and behavior. Thus, the use of TLR4-agonists in the first hours after injury may be an option to attenuate the sequelae of neuro-trauma.
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