NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1

作者全名："He, Qi; Meng, Changchang; Jia, Mengjie; Tan, Junyi; Huang, Keli; Gan, Hui; Li, Lingyu; Zhao, Jing"

作者地址："[He, Qi; Jia, Mengjie; Tan, Junyi; Huang, Keli; Zhao, Jing] Chongqing Med Univ, Dept Pathophysiol, Chongqing 400010, Peoples R China; [He, Qi; Jia, Mengjie; Tan, Junyi; Huang, Keli; Gan, Hui; Li, Lingyu; Zhao, Jing] Chongqing Med Univ, Ctr Neurosci Res, Chongqing 400016, Peoples R China; [Meng, Changchang] Zunyi Med Univ, Zhuhai Campus, Zhuhai 519000, Guangdong, Peoples R China; [Li, Lingyu] Chongqing Med Univ, Dept Pathol, Chongqing 400010, Peoples R China"

通信作者："Zhao, J (通讯作者)，Chongqing Med Univ, Dept Pathophysiol, Chongqing 400010, Peoples R China.; Li, LY; Zhao, J (通讯作者)，Chongqing Med Univ, Ctr Neurosci Res, Chongqing 400016, Peoples R China.; Li, LY (通讯作者)，Chongqing Med Univ, Dept Pathol, Chongqing 400010, Peoples R China."

来源：NEUROBIOLOGY OF DISEASE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001182374300001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：192

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Ischemic stroke; Innate inflammation; Inflammasome; NLRP6; Pro-caspase-1; NLRP3; NLRC4

摘要："Innate inflammation is crucial for ischemic stroke development. NLRP6, a nucleotide-binding and oligomerization domain-like receptors (NLRs) family member, regulates innate inflammation. Whether NLRP6 regulates neurological damage and neuroinflammation during ischemic stroke remains unclear. We report that NLRP6 is abundantly expressed in microglia and significantly upregulated in the ischemic brain. The brain injury severity was alleviated in NLRP6-deficient mice after ischemic stroke, as evidenced by reduced cerebral infarct volume, decreased neurological deficit scores, improved histopathological morphological changes, ameliorated neuronal denaturation, and relief of sensorimotor dysfunction. In the co-culture OGD/R model, NLRP6 deficiency prevented neuronal death and attenuated microglial cell injury. NLRP6 deficiency blocked several NLRs inflammasomes' activation and abrogated inflammasome-related cytokine production by decreasing the expression of the common effector pro-caspase-1. NLRP6 deficiency reduced pro-caspase-1's protein level by inducing proteasomal degradation. These findings confirm the neuroprotective role of NLRP6 deficiency in ischemic stroke and its underlying regulation mechanism in neuroinflammation and provide a potential therapeutic target for ischemic stroke."

基金机构："National Natural Science Foundation of China [82071305, 81971217]; Youth Fund of the National Natural Science Foundation of China [82302474, 82301512]; Natural Science Foundation of Chongqing Science and Technology Committee, China [CSTC2021jcyj-msxmX0001]; National Clinical Medical Research Centre [YBXM-2019-17]; Chongqing Postdoctoral Science Foundation [CST2023NSCQBHX0121, CSTB2022NSCQ-BHX0629]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (Nos. 82071305 and 81971217), the Youth Fund of the National Natural Science Foundation of China (Nos. 82302474 and 82301512), the Natural Science Foundation of Chongqing Science and Technology Committee, China (No. CSTC2021jcyj-msxmX0001), the National Clinical Medical Research Centre (YBXM-2019-17), and the Chongqing Postdoctoral Science Foundation (No.CST2023NSCQBHX0121 and CSTB2022NSCQ-BHX0629)."