NLRP3-GSDMD-dependent IL-1I3 Secretion from Microglia Mediates Learning and Memory Impairment in a Chronic Intermittent Hypoxia-induced Mouse Model

作者全名："Li, Chaohong; Zhao, Zhen; Jin, Jiahao; Zhao, Chenlu; Zhao, Baosheng; Liu, Yuzhen"

作者地址："[Li, Chaohong; Zhao, Zhen; Jin, Jiahao; Zhao, Chenlu; Liu, Yuzhen] Xinxiang Med Univ, Life Sci Res Ctr, Henan Key Lab Neurorestoratol, Affiliated Hosp 1, Weihui 453100, Henan, Peoples R China; [Li, Chaohong] Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 2, Chongqing 400000, Peoples R China; [Zhao, Baosheng] Xinxiang Med Univ, Dept Thorac Surg, Affiliated Hosp 1, Weihui 453100, Henan, Peoples R China"

通信作者："Liu, YZ (通讯作者)，Xinxiang Med Univ, Life Sci Res Ctr, Henan Key Lab Neurorestoratol, Affiliated Hosp 1, Weihui 453100, Henan, Peoples R China."

来源：NEUROSCIENCE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001169128000001

JCR分区：Q2

影响因子：2.9

年份：2024

卷号：539

期号：　

开始页：51

结束页：65

文献类型：Article

关键词：chronic intermittent hypoxia; cognitive impairment; NLRP3 inflammasome; gasdermin D; non-pyroptosis

摘要："caused by chronic intermittent hypoxia (CIH) plays an important role in cognitive deficits in patients with obstructive sleep apnea. However, the precise underlying mechanism remains unclear. This study investigated whether the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is involved in CIH-induced spatial learning and memory impairment in mice, and the possible underlying upstream and downstream mechanisms. The C57BL/6 male mice were exposed to CIH (21% O2-6% O2, 4 min/cycle, 8 h/day) for 9 weeks to investigate the role of NLRP3 in CIH-induced spatial learning and memory impairment in mice. BV2 cells were exposed to intermittent hypoxia (21% O2-1% O2, 90 min/cycle) for 48 h to investigate the possible mechanisms in vitro. We found that: 1) inhibition of NLRP3 inflammasome activation improved CIH-induced spatial learning and memory impairment in mice. 2) CIH damaged hippocampal neurons but increased the number of microglia in mice hippocampi; CIH activated microglia-specific NLRP3 inflammasome, leading to upregulation of matured IL-1I3 and N-GSDMD. 3) intermittent hypoxia activated NLRP3 inflammasome via the ROS-NF-KB signaling pathway to promote the release of matured IL-1I3 from microglia in a GSDMD-dependent manner without pyroptosis. 4) The IL-1I3 released from microglia might impair the synaptic plasticity of hippocampal CA3-CA1 synapses by acting on IL-1 receptors in hippocampal neurons. Our findings reveal that ROS-NF-KB-NLRP3 inflammasome-GSDMD dependent IL-1I3 release from microglia may participate in CIH-induced spatial learning and memory impairment by acting on hippocampal neuronal IL-1 receptor, leading to synaptic plasticity impairment.(c) 2023 IBRO. Published by Elsevier Ltd. All rights reserved."

基金机构：National Natural Science Foundation of China [81973988]; Henan Provincial Science and Technology Research Project [222102310295]; Henan Plan of the Medical Science and Technology Research [LHGJ20200499]; Henan Key Laboratory of Neurorestoratology Foundation [HNSJXF-2021-014]

基金资助正文："<BOLD>Funding</BOLD> This work was supported by National Natural Science Foundation of China to YL [grant number 81973988] , Henan Provincial Science and Technology Research Project to CL [grant number 222102310295] , Henan Plan of the Medical Science and Technology Research to CL [grant number LHGJ20200499] , and Henan Key Laboratory of Neurorestoratology Foundation to YL [grant number HNSJXF-2021-014] ."