NPAS4 Exacerbates Pyroptosis via Transcriptionally Regulating NLRP6 in the Acute Phase of Intracerebral Hemorrhage in Mice

作者全名："Jian, Dan; Qin, Le; Gan, Hui; Zheng, Shuyue; Xiao, Han; Duan, Yuhao; Zhang, Mi; Liang, Ping; Zhao, Jing; Zhai, Xuan"

作者地址："[Jian, Dan; Qin, Le; Gan, Hui; Xiao, Han; Duan, Yuhao; Zhang, Mi; Liang, Ping; Zhai, Xuan] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurosurg, Childrens Hosp,Minist Educ,Key Lab Child Dev & Dis, Chongqing 400010, Peoples R China; [Jian, Dan; Qin, Le; Zheng, Shuyue; Duan, Yuhao; Zhang, Mi; Zhao, Jing] Chongqing Med Univ, Ctr Neurosci Res, Sch Basic Med, Chongqing 400016, Peoples R China"

通信作者："Zhai, X (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurosurg, Childrens Hosp,Minist Educ,Key Lab Child Dev & Dis, Chongqing 400010, Peoples R China.; Zhao, J (通讯作者)，Chongqing Med Univ, Ctr Neurosci Res, Sch Basic Med, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

ESI学科分类：CHEMISTRY

WOS号：WOS:000987570600001

JCR分区：Q1

影响因子：4.9

年份：2023

卷号：24

期号：9

开始页：　

结束页：　

文献类型：Article

关键词：intracerebral hemorrhage; pyroptosis; NPAS4; NLRP6 inflammasome

摘要："Intracerebral hemorrhage (ICH) is a severe cerebrovascular disease with a high disability rate and high mortality, and pyroptosis is a type of programmed cell death in the acute phase of ICH. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is a specific transcription factor highly expressed in the nervous system, yet the role of NPAS4 in ICH-induced pyroptosis is not fully understood. NLR family Pyrin-domain-containing 6 (NLRP6), a new member of the Nod-like receptor family, aggravates pyroptosis via activating cysteine protease-1 (Caspase-1) and Caspase-11. In this study, we found that NPAS4 was upregulated in human and mouse peri-hematoma brain tissues and peaked at approximately 24 h after ICH modeling. Additionally, NPAS4 knockdown improved neurologic dysfunction and brain damage induced by ICH in mice after 24 h. Meanwhile, inhibiting NPAS4 expression reduced the levels of myeloperoxidase (MPO)-positive cells and Caspase-1/TUNEL-double-positive cells and decreased cleaved Caspase-1, cleaved Caspase-11, and N-terminal GSDMD levels. Consistently, NPAS4 overexpression reversed the above alternations after ICH in the mice. Moreover, NPAS4 could interact with the Nlrp6 promoter region (-400--391 bp and -33--24 bp) and activate the transcription of Nlrp6. Altogether, our study demonstrated that NPAS4, as a transcription factor, can exacerbate pyroptosis and transcriptionally activate NLRP6 in the acute phase of intracerebral hemorrhage in mice."

基金机构："National Natural Science Foundation of China [82071305, 81971217]; Natural Science Foundation of Chongqing Science and Technology Committee, China [CSTC2021jcyj-msxmX0001]; China Postdoctoral Science Foundation [YBXM-2019-17]; project of National Clinical Medical Research Center; [2022MD723734]"

基金资助正文："This research was supported by the National Natural Science Foundation of China (grant numbers: 82071305, 81971217); the Natural Science Foundation of Chongqing Science and Technology Committee, China (CSTC2021jcyj-msxmX0001); the project of National Clinical Medical Research Center (YBXM-2019-17); and the China Postdoctoral Science Foundation (2022MD723734)."