HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.

Abstract

BACKGROUND:

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. 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.

METHODS:

Mice 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.

RESULTS:

By 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.

CONCLUSION:

NLRP3 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.

• Authors: Si-Wei Tan, Yan Zhao, Ping Li, Ya-Lei Ning, Zhi-Zhong Huang, Nan Yang, Dong Liu, Yuan-Guo Zhou
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 18 Issue 1 Pg. 241 (Oct 19 2021) ISSN: 1742-2094 [Electronic] England
• PMID: 34666797 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• HMGB1 Protein
• HMGB1 protein, mouse
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse

Topics

• Animals
• Brain Injuries, Traumatic (metabolism, pathology)
• Cells, Cultured
• Cerebral Cortex (metabolism, pathology)
• Coculture Techniques
• Cognitive Dysfunction (metabolism, pathology)
• Excitatory Postsynaptic Potentials (physiology)
• HMGB1 Protein (metabolism)
• Hippocampus (metabolism, pathology)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Organ Culture Techniques