Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in 3xTg AD mice

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. Recent studies have found that TBI triggers activation of NLRP3 inflammasome in the brain whereas the NLRP3 inflammasome plays an important role in pathogenesis of AD. To evaluate the influence of TBI on the immune response and the importance of the NLRP3 inflammasome in mediating this process we have examined the immune profiles in the brain using a novel transgenic AD mouse line with the NLRP3 gene deleted. Briefly, a group of 3xTg and 3xTg/NLRP3 ^-/- mice received a moderate TBI in the form of lateral fluid percusive injury FPI or sham surgery at the age of 4 months old, an age before the onset of AD. Injury-induced changes in immune profiling were assessed using flow cytometry, real-time quantitative PCR, or Western blot at the acute and subacute stages following TBI. We found that TBI altered immune profiles in 3xTg mice and NLRP3 gene knock out counteracts the injury effect with a significant sex-related difference. More specifically, at the acute stage after TBI in both male and female mice, TBI induced a significant infiltration of neutrophils, macrophages and γδ T-cells in the brains of 3xTg mice, however, NLRP3 knock down significantly blocked this injury effect in males and less so in females. We also found that NLRP3 gene knock down counteracted TBI-enhanced inflammatory cytokine IL1-β, TNF-α, and IL-17f expression. The abnormal immune profiling was not significant at 7 days post-injury, however, changes in cerebral vascular associated proteins including GFAP, AQP4, CD31, Occludin were observed in related to injury, NLRP3 and sex. In conclusion, our study has confirmed that TBI significantly alters immune profiles and vascular integrity in the context of predisposition of AD and the NLRP3 inflammasome is important in mediating these TBI-induced changes. Sex-related differences warrant further evaluation to define the role of NLRP3-related immune response and vascular pathology as a result to TBI and the predisposition to AD development.