Abstract
BackgroundCognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Although classical inflammatory pathways have been well-documented in the late stage of TBI (4–8 weeks post-injury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear.MethodsMice lacking the gene encoding for NLRP3 (NLRP3-knockout mice) and their wild-type littermates were used in a controlled cortical impact model of TBI. Levels of NLRP3 inflammasome and inflammatory factors such as IL-1β and HMGB1 were detected in post-injury hippocampal tissue, as well as long-term potentiation. Behaviors were assessed by T-maze test, novel object recognition, and nesting tests. Glycyrrhizin was used to antagonize HMGB1. Calcium imaging were performed on primary neuronal cultures.ResultsBy using the NLRP3-knockout TBI model, we found that the continuous activation of the NLRP3 inflammasome and high mobility group box 1 (HMGB1) release were closely related to cognitive impairment. We also found that inhibition of HMGB1 improved LTP reduction and cognitive function by increasing the phosphorylation level of the NMDAR1 subunit at serine 896 while reducing NLRP3 inflammasome activation.ConclusionNLRP3 inflammasome damages memory in the late stage of TBI primarily through HMGB1 upregulation and provides an explanation for the long-term progression of cognitive dysfunction.
Highlights
Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation
We studied a late-stage TBI model (4–8 weeks) with NLRP3-knockout (KO) and wild-type (WT) mice and conducted behavioral tests, field excitatory postsynaptic potential recordings and molecular biology analyses to confirm that the continuous activation of the NLRP3 inflammasome and elevated high mobility group box 1 (HMGB1) are the key causes of TBI-induced cognitive impairment
The NLRP3 inflammasome is continuously activated in the hippocampus–prefrontal cortex circuit for up to 8 weeks after TBI, followed by elevated levels of HMGB1 Because the injured lateral hippocampus turned into liquefactive necrosis after 4 w, the contralateral hippocampus and PFC were used in this study
Summary
Cognitive impairment in the late stage of traumatic brain injury (TBI) is associated with the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome, which plays an important role in neuroinflammation. Classical inflammatory pathways have been well-documented in the late stage of TBI (4–8 weeks postinjury), the mechanism by which the NLRP3 inflammasome impairs cognition is still unclear. Traumatic brain injury (TBI) is a common cause of acute lethality, but often progresses to cognitive disorder in the late stage [1]. The neuroinflammation caused by the NOD-, LRR and pyrin domain-containing protein 3 (NLRP3) inflammasome and its role in cognitive impairment are receiving increasing attention. One of the main issues is that inflammatory factors, such as IL-1β and IL-18, tend to return to baseline levels within 3 days of TBI [9], but the formation and development of cognitive impairment and neurodegeneration continue
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