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Tlr4 Inhibition with C34 Leads to an Increase in Infiltrating Anti-inflammatory Monocytes and Improved Cognitive Outcomes
Young Chun, Simon Rahal, William Fulton, Chhinder Sodhi Sodhi, David J. Hackam, *Isam W. Nasr
Johns Hopkins, Baltimore, MD

Background (issue):Traumatic brain injury (TBI) induces a neuroinflammatory response that activates the innate immune system, specifically Toll-like receptor 4 (TLR4) signaling. This triggers the TBI-induced neuroinflammatory cascade. We hypothesize that TLR4 inhibition with C34 attenuates the acute neuroinflammatory response leading to improved cognitive outcomes.
Methods:

A murine controlled cortical impact model was used. The experimental groups: wild-type (WT), WT+C34. Cell-sorting was used to isolate monocytes and microglia from the brain. RT-PCR quantified cytokine gene expression. Morris Water Maze (MWM) was used to assess cognitive outcomes. Statistical analysis: Student’s T-test and One-way ANOVA.
Findings:
The C34 (TLR4 inhibitor) treatment group showed a marked increase in infiltrating monocytes on post-injury day (PID) 7. PID 1, infiltrating monocytes had significantly higher expression of IL-10 (31.66±5.013, n=5) but decreased expression of TNFɑ (512.5±59.35, n=5) compared to the expression in brain microglia: IL-10 (2.748±0.3728, n=5), and TNFɑ (1220±166.8, n=5). On PID 7, the infiltrating monocytes had higher expression of IL-10 (7.068±1.79, n=4) but decreased expression of IL-6 (8.898±0.7059, n=5) and TNFɑ (92.64±20.07, n=4) compared to microglia: IL-10 (1.604±0.4127, n=5), IL-6 (85.68±12.82, n=5), and TNFɑ (512.6±80.31, n=5). The treatment group showed significantly improved cognitive behavior. MWM showed improved latency in week 1 and platform entries in week 4 (p=0.026).
Conclusions (implications for practice):
Infiltrating monocytes play a key role in early and delayed immune responses to TBI. These monocytes displayed an anti-inflammatory gene expression profile in the injured brain compared to resident microglia. The increased number of infiltrating anti-inflammatory monocytes may contribute to improved cognitive outcomes in C34-treated mice.


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