HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.
HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury.
复制标题
HMGB1介导NLRP3炎症小体引起的脑外伤晚期认知障碍
DOI：
10.1186/s12974-021-02274-0
复制
发表时间：
2021-10-19
影响因子：
9.3
通讯作者：
Zhou YG
中科院分区：
文献类型：
--
作者：
Tan SW;Zhao Y;Li P;Ning YL;Huang ZZ;Yang N;Liu D;Zhou YG
研究背景脑外伤（traumatic brain injury，TBI）晚期认知功能障碍与NOD-、LRR和pyrin domain containing protein 3（NLRP 3）炎性小体有关，NLRP 3在神经炎症中起重要作用。虽然经典的炎症途径已被充分记录在TBI的后期（4-8周后损伤），NLRP 3炎性小体损害认知的机制仍不清楚。MethodsMouse缺乏NLRP 3（NLRP 3基因敲除小鼠）的基因编码和他们的野生型同窝出生的TBI的控制皮质影响模型中使用。检测损伤后海马组织中NLRP 3炎性小体、IL-1β、HMGB 1等炎性因子的表达及长时程增强。通过T-迷宫测试、新物体识别和嵌套测试评估行为。用甘草甜素拮抗HMGB 1。钙成像进行原代神经元cultures.ResultsBy使用NLRP 3敲除TBI模型，我们发现，NLRP 3炎性小体和高迁移率族蛋白1（HMGB 1）释放的持续激活与认知功能障碍密切相关。结论NLRP 3炎性小体主要通过上调HMGB 1的表达而损害TBI后期的记忆功能，并可能为TBI认知功能障碍的长期进展提供了一种解释。
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.
登录
查看更多内容
影响因子：
5.6
作者：
Irrera N;Pizzino G;Calò M;Pallio G;Mannino F;Famà F;Arcoraci V;Fodale V;David A;Francesca C;Minutoli L;Mazzon E;Bramanti P;Squadrito F;Altavilla D;Bitto A
通讯作者：
Bitto A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Ramlackhansingh, Anil F.;Brooks, David J.;Sharp, David J.
通讯作者：
Sharp, David J.
影响因子：
15.9
作者：
Guo, De-Huang;Yamamoto, Masaki;Stranahan, Alexis M.
通讯作者：
Stranahan, Alexis M.
影响因子：
2
作者：
Arciniegas, David B.;Held, Kerri;Wagner, Peter
通讯作者：
Wagner, Peter