GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice
Abstract Background Temporal 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 gasdermi...
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-023-02876-w |
| _version_ | 1797557560351391744 |
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| author | Xiaoxia Yang Qingqing Cao Yi Guo Jingchuan He Demei Xu Aolei Lin |
| author_facet | Xiaoxia Yang Qingqing Cao Yi Guo Jingchuan He Demei Xu Aolei Lin |
| author_sort | Xiaoxia Yang |
| collection | DOAJ |
| description | Abstract Background Temporal 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. Methods To 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 P2Y12R agonist 2MeSADP. Results GSDMD 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 P2Y12R selective agonist, 2MeSADP, enhanced the migration and phagocytic activity of microglia. Conclusions Our 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. |
| first_indexed | 2024-03-10T17:19:37Z |
| format | Article |
| id | doaj.art-c94783463c234aeea3322f64df4301ac |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:37Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c94783463c234aeea3322f64df4301ac2023-11-20T10:24:19ZengBMCJournal of Neuroinflammation1742-20942023-08-0120111510.1186/s12974-023-02876-wGSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE miceXiaoxia Yang0Qingqing Cao1Yi Guo2Jingchuan He3Demei Xu4Aolei Lin5Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General HospitalDepartment of Neurology, Bishan Hospital of Chongqing Medical University, Bishan Hospital of ChongqingDepartment of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of ChinaDepartment of Otorhinolaryngology Head and Neck Surgery, Tianjin Huanhu HospitalDepartment of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Neurology, Tianjin Neurological Institute, Tianjin Medical University General HospitalAbstract Background Temporal 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. Methods To 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 P2Y12R agonist 2MeSADP. Results GSDMD 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 P2Y12R selective agonist, 2MeSADP, enhanced the migration and phagocytic activity of microglia. Conclusions Our 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.https://doi.org/10.1186/s12974-023-02876-wGSDMDPyroptosisPhagocytic activity of microgliaP2Y12RTemporal lobe epilepsy |
| spellingShingle | Xiaoxia Yang Qingqing Cao Yi Guo Jingchuan He Demei Xu Aolei Lin GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice Journal of Neuroinflammation GSDMD Pyroptosis Phagocytic activity of microglia P2Y12R Temporal lobe epilepsy |
| title | GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice |
| title_full | GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice |
| title_fullStr | GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice |
| title_full_unstemmed | GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice |
| title_short | GSDMD knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in TLE mice |
| title_sort | gsdmd knockdown attenuates phagocytic activity of microglia and exacerbates seizure susceptibility in tle mice |
| topic | GSDMD Pyroptosis Phagocytic activity of microglia P2Y12R Temporal lobe epilepsy |
| url | https://doi.org/10.1186/s12974-023-02876-w |
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