炎症体
小胶质细胞
神经炎症
医学
上睑下垂
半胱氨酸蛋白酶1
炎症
蛋白激酶A
神经科学
细胞生物学
激酶
药理学
免疫学
化学
癌症研究
生物
作者
Jun He,Taotao Liu,Yue Li,Xinning Mi,Dengyang Han,Ning Yang,Lei Chen,Yitong Li,Jingshu Hong,Chongshen Kuang,Yi Yuan,Yanyan Cao,Yongzheng Han,Chengmei Shi,Zhengqian Li,Xiangyang Guo
标识
DOI:10.1016/j.intimp.2021.107962
摘要
Delayed neurocognitive recovery (dNCR) is a prevalent complication after surgery in older adults. Neuroinflammation plays a pivotal role in the pathogenesis of dNCR. Recently,compelling evidence suggests that theinvolvement of microglia pyroptosis in the regulation of neuroinflammation in neurologicaldiseases. Nevertheless, the exact role of microglia pyroptosis in dNCR remains elusive. In the study, in vitro and in vivo models of dNCR were used to examine the potential effects of the mitogen‑activated protein kinase signaling pathway on Nod-like receptor protein 3 (NLRP3) inflammasome-mediated microglia pyroptosis and cognitive deficits following surgery. In vivo, we observed surgery-induced upregulation of phosphorylated (p)-c-Jun N-terminal kinases (JNK) in microglia and subsequently NLRP3 inflammasome activation, pyroptosis, and inflammatory cytokines release in mice hippocampus. Interestingly, JNK inhibitor SP600125 significantly attenuated surgery-induced cognitive impairments through inhibiting pyroptosis, inflammatory responses, and reducing immunoreactivity of NLRP3 and gasdermin D N terminus (GSDMD-N) in hippocampal microglia. In vitro, NLRP3 inflammasome- and pyroptosis-associated proteins and immunoreactivity of NLRP3, GSDMD-N, and interleukin-1β were activated in BV2 microglial cells following lipopolysaccharide (LPS) stimulation. These effects were significantly suppressed in BV2 cells by SP600125 treatment. Furthermore, treatment with NLRP3 specific inhibitor, MCC950, attenuated microglia pyroptosis induced by LPS, but did not rescue LPS-induced increased expression of p-JNK. These results indicate that the JNK pathway is largely upstream of the NLRP3 inflammasome, which exerts a crucial regulatory impact on microglia pyroptosis and inflammatory responses, thus providing a promising avenue to prevent dNCR.
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