Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice

doi:10.1016/j.bbadis.2024.167137

科研成果详情

题名	Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice
作者	Lin, Qi-Cheng 1,2,3; Wang, Jiao1,2,3; Wang, Xin-Lin1,2,3; Pan, Chi1,2,3; Jin, Shao-Wu 1,2,3; Char, Steven 4; Tao, Yuan-Xiang 1,4; Cao, Hong1,2,3; Li, Jun1,2,3
发表日期	2024-06
发表期刊	Biochimica et Biophysica Acta - Molecular Basis of Disease; 影响因子和分区
语种	英语
原始文献类型	Article
其他关键词	INFLAMMATORY RESPONSE ; COGNITIVE IMPAIRMENT ; DEACETYLASES ; PROTEINS
摘要	Background: Postoperative Cognitive Dysfunction (POCD) has attracted increased attention, but its precise mechanism remains to be explored. This study aimed to figure out whether HDAC6 could regulate NLRP3-induced pyroptosis by modulating the functions of HSP70 and HSP90 in microglia to participate in postoperative cognitive dysfunction in aged mice. Methods: Animal models of postoperative cognitive dysfunction in aged mice were established by splenectomy under sevoflurane anesthesia. Morris water maze was used to examine the cognitive function and motor ability. Sixteen-months-old C57BL/6 male mice were randomly divided into six groups: control group (C group), sham surgery group (SA group), splenectomy group (S group), splenectomy + HDAC6 inhibitor ACY-1215 group (ACY group), splenectomy + HDAC6 inhibitor ACY-1215 + HSP70 inhibitor Apoptozole group (AP group), splenectomy + solvent control group (SC group). The serum and hippocampus of mice were taken after mice were executed. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, cleaved-Caspase-1 (P20), IL-1β were detected by western blotting. Serum IL-1β, IL-6 and S100β were measured using ELISA assay, and cell localization of HDAC6 was detected by immunofluorescence. In vitro experiments, BV2 cells were used to validate whether this mechanism worked in microglia. The protein levels of HDAC6, HSP90, HSP70, NLRP3, GSDMD-N, P20, IL-1β were detected by western blotting and the content of IL-1β in the supernatant was measured using ELISA assay. The degree of acetylation of HSP90, the interaction of HSP70, HSP90 and NLRP3 were analyzed by coimmunoprecipitation assay. Results: Splenectomy under sevoflurane anesthesia in aged mice could prolong the escape latency, reduce the number of crossing platforms, increase the expression of HDAC6 and activate the NLRP3 inflammasome to induce pyroptosis in hippocampus microglia. Using ACY-1215 could reduce the activation of NLRP3 inflammasome, the pyroptosis of microglia and the degree of spatial memory impairment. Apoptozole could inhibit the binding of HSP70 to NLRP3, reduce the degradation of NLRP3 and reverse the protective effect of HDAC6 inhibitors. The results acquired in vitro experiments closely resembled those in vivo, LPS stimulation led to the pyroptosis of BV2 microglia cells and the release of IL-1β due to the activation of the NLRP3 inflammasome, ACY-1215 showed the anti-inflammatory effect and Apoptozole exerted the opposite effect. Conclusions: Our findings suggest that hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.
资助项目	Natural Science Foundation of Zhejiang Province[Y21H090095];
出版者	ELSEVIER
ISSN	0925-4439
EISSN	1879-260X
卷号	1870 期号:5
DOI	10.1016/j.bbadis.2024.167137
页数	10
WOS类目	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS记录号	WOS:001219668200001
收录类别	SCOPUS ; SCIE ; PUBMED
URL	查看原文
PubMed ID	38527593
SCOPUSEID	2-s2.0-85189036279
通讯作者地址	[Cao, Hong]Department of Anesthesiology and Perioperative Medicine,The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,China
Scopus学科分类	Molecular Medicine;Molecular Biology
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/212612
专题	第二临床医学院、附属第二医院、育英儿童医院附属第二医院_麻醉重点学科实验室
通讯作者	Cao, Hong; Li, Jun
作者单位	1.Department of Anesthesiology and Perioperative Medicine,The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University,Zhejiang,Wenzhou,China; 2.Key Laboratory of Anesthesiology of Zhejiang Province,Wenzhou Medical University,Zhejiang,Wenzhou,China; 3.Key Laboratory of Pediatric Anesthesiology,Ministry of Education,Wenzhou Medical University,Zhejiang,Wenzhou,China; 4.Department of Anesthesiology,Rutgers New Jersey Medical School,Newark,United States
第一作者单位	第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院; 温州医科大学
通讯作者单位	第二临床医学院，附属第二医院、育英儿童医院; 附属第二医院
第一作者的第一单位	第二临床医学院，附属第二医院、育英儿童医院
推荐引用方式 GB/T 7714	Lin, Qi-Cheng,Wang, Jiao,Wang, Xin-Lin,et al. Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice[J]. Biochimica et Biophysica Acta - Molecular Basis of Disease;,2024,1870(5).
APA	Lin, Qi-Cheng., Wang, Jiao., Wang, Xin-Lin., Pan, Chi., Jin, Shao-Wu., ... & Li, Jun. (2024). Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice. Biochimica et Biophysica Acta - Molecular Basis of Disease;, 1870(5).
MLA	Lin, Qi-Cheng,et al."Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice".Biochimica et Biophysica Acta - Molecular Basis of Disease; 1870.5(2024).