GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice

作者全名："Yang, Xiaoxia; Cao, Qingqing; Guo, Yi; He, Jingchuan; Xu, Demei; Lin, Aolei"

作者地址："[Yang, Xiaoxia; Lin, Aolei] Tianjin Med Univ Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Anshan Rd 154, Tianjin 300052, Peoples R China; [Cao, Qingqing] Chongqing Med Univ, Bishan Hosp Chongqing, Dept Neurol, Bishan Hosp, 9 Shuangxing Rd, Chongqing 402760, Peoples R China; [Guo, Yi] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Neurol, 32 W Sec 2, 1st Ring Rd, Chengdu 610072, Sichuan, Peoples R China; [He, Jingchuan] Tianjin Huanhu Hosp, Dept Otorhinolaryngol Head & Neck Surg, 6 Jizhao Rd Jinnan Dist, Tianjin 300350, Peoples R China; [Xu, Demei] Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Neurol, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："Lin, AL (通讯作者)，Tianjin Med Univ Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Anshan Rd 154, Tianjin 300052, Peoples R China."

来源：JOURNAL OF NEUROINFLAMMATION

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001053726400001

JCR分区：Q1

影响因子：9.3

年份：2023

卷号：20

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：GSDMD; Pyroptosis; Phagocytic activity of microglia; P2Y(12)R; Temporal lobe epilepsy

摘要："BackgroundTemporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Phagocytic activity of microglia is essential for clearing apoptotic neuronal debris, allowing for repair and regeneration. Our previous research has shown that gasdermin D (GSDMD)-mediated pyroptosis is involved in the pathogenesis of TLE. However, whether GSDMD-mediated pyroptosis influences the accumulation of apoptotic neurons remains unclear. Therefore, the present study was designed to investigate whether phagocytic activity of microglia is involved in GSDMD-mediated pyroptosis and the pathogenesis of TLE.MethodsTo establish a TLE model, an intra-amygdala injection of kainic acid (KA) was performed. The Racine score and local field potential (LFP) recordings were used to assess seizure severity. Neuronal death in the bilateral hippocampus was assessed by Nissl staining and TUNEL staining. Microglial morphology and phagocytic activity were detected by immunofluorescence and verified by lipopolysaccharide (LPS) and the P2Y(12)R agonist 2MeSADP.ResultsGSDMD knockdown augmented the accumulation of apoptotic neurons and seizure susceptibility in TLE mice. Microglia activated and transition to the M1 type with increased pro-inflammatory cytokines. Furthermore, GSDMD knockdown attenuated the migration and phagocytic activity of microglia. Of note, LPS-activated microglia attenuated seizure susceptibility and the accumulation of apoptotic neurons in TLE after GSDMD knockdown. A P2Y(12)R selective agonist, 2MeSADP, enhanced the migration and phagocytic activity of microglia.ConclusionsOur results demonstrate that GSDMD knockdown exacerbates seizure susceptibility and the accumulation of apoptotic neurons by attenuating phagocytic activity of microglia. These findings suggest that GSDMD plays a protective role against KA-induced seizure susceptibility."

基金机构：We thank Professor Liu Qiang for the guidance on article writing and revision.

基金资助正文：We thank Professor Liu Qiang for the guidance on article writing and revision.