Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in mice with a genetic background for AD.

Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimer's disease (AD) and related dementia. In both TBI and AD, inflammation plays a pivotal role. It is known that the NLRP3 inflammasome plays an important role in AD pathogenesis while TBI triggers activation of the NLRP3 inflammasome in the brain. To evaluate the importance of the NLRP3 inflammasome in mediating the TBI-induced immune response in animals with a genetic background for AD, we have examined immune profiles in the brain using a novel transgenic mouse line at 3xTg background with the NLRP3 gene deleted. Briefly, a group of 4 months old male and female 3xTg and 3xTg/NLRP3-/- mice received a moderate lateral fluid percussive injury or sham. Immune cell phenotypes and cytokine gene expression were assessed at 3- and 7-days post injury (dpi). We found that NLRP3 gene deletion counteracted injury-induced alteration of the immune response in 3xTg mice with a significant sex-related difference. Specifically, TBI induced a significant brain infiltration of neutrophils, macrophages and γδ T-cells in 3xTg mice in both sexes at 3dpi, and NLRP3 gene deletion blocked this injury effect only in males not in females. NLRP3 gene deletion also blocked injury-enhanced IL-1β, TNF-α gene expression in male mice, but not in female mice. In conclusion, our study has confirmed that TBI significantly alters the immune response in 3xTg mice and NLRP3 inflammasome is important in mediating these TBI-induced changes with significant sex-related differences.