Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway
Epilepsy is a neurological disease and approximately 30% of patients have failed to respond to current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns and been regarded as the novel treatment strategy in epilepsy, but the target molecules require further research....
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MDPI AG
2023-02-01
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| Series: | Brain Sciences |
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| Online Access: | https://www.mdpi.com/2076-3425/13/2/262 |
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| author | Xinlin Li Rong Zhou Hui Peng Jing Peng Qiaoling Li Meng Mei |
| author_facet | Xinlin Li Rong Zhou Hui Peng Jing Peng Qiaoling Li Meng Mei |
| author_sort | Xinlin Li |
| collection | DOAJ |
| description | Epilepsy is a neurological disease and approximately 30% of patients have failed to respond to current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns and been regarded as the novel treatment strategy in epilepsy, but the target molecules require further research. Pyruvate kinase isoform 2 (PKM2) is well studied in peripheral inflammation, but its role in epilepsy neuroinflammation remains unclear. We knocked down microglia PKM2 in the hippocampus using a stereotaxic adeno-associated virus (AAV) microinjection and established a pilocarpine-induced status epilepticus (PISE) model. Racine score was used to evaluate the seizure grade. Next, we used WB, Multiplex tyramide signal amplification (TSA) staining and other methods to determine neuroinflammation and the complement component 3 (C3)–C3aR interaction in primary microglia. Results showed that microglia PKM2 knockdown reduced epilepsy grade and rescued neuron loss. Mechanistically, PKM2 knockdown inhibited microglia activation and inflammation factor secretion through suppressing p65 expression and phosphorylation. The reduced microglia C1q, TNF-α, and IL-1α were responsible for the decreased astrocyte C3 expression and the following neuron damage caused by the C3–C3aR interaction. Our data suggest that microglia PKM2 inhibition ameliorates neuroinflammation and neuron loss through C3-C3aR interaction in epilepsy, which provides an attractive target for the intervention of damaged neuron-glia crosstalk in epilepsy. |
| first_indexed | 2024-03-11T09:05:25Z |
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| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-11T09:05:25Z |
| publishDate | 2023-02-01 |
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| spelling | doaj.art-dc0b264d075e466bab5be0962847b99e2023-11-16T19:28:33ZengMDPI AGBrain Sciences2076-34252023-02-0113226210.3390/brainsci13020262Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling PathwayXinlin Li0Rong Zhou1Hui Peng2Jing Peng3Qiaoling Li4Meng Mei5Department of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaDepartment of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaDepartment of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaDepartment of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaDepartment of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaDepartment of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430015, ChinaEpilepsy is a neurological disease and approximately 30% of patients have failed to respond to current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns and been regarded as the novel treatment strategy in epilepsy, but the target molecules require further research. Pyruvate kinase isoform 2 (PKM2) is well studied in peripheral inflammation, but its role in epilepsy neuroinflammation remains unclear. We knocked down microglia PKM2 in the hippocampus using a stereotaxic adeno-associated virus (AAV) microinjection and established a pilocarpine-induced status epilepticus (PISE) model. Racine score was used to evaluate the seizure grade. Next, we used WB, Multiplex tyramide signal amplification (TSA) staining and other methods to determine neuroinflammation and the complement component 3 (C3)–C3aR interaction in primary microglia. Results showed that microglia PKM2 knockdown reduced epilepsy grade and rescued neuron loss. Mechanistically, PKM2 knockdown inhibited microglia activation and inflammation factor secretion through suppressing p65 expression and phosphorylation. The reduced microglia C1q, TNF-α, and IL-1α were responsible for the decreased astrocyte C3 expression and the following neuron damage caused by the C3–C3aR interaction. Our data suggest that microglia PKM2 inhibition ameliorates neuroinflammation and neuron loss through C3-C3aR interaction in epilepsy, which provides an attractive target for the intervention of damaged neuron-glia crosstalk in epilepsy.https://www.mdpi.com/2076-3425/13/2/262epilepsyneural networkneuroinflammationPKM2C3 |
| spellingShingle | Xinlin Li Rong Zhou Hui Peng Jing Peng Qiaoling Li Meng Mei Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway Brain Sciences epilepsy neural network neuroinflammation PKM2 C3 |
| title | Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway |
| title_full | Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway |
| title_fullStr | Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway |
| title_full_unstemmed | Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway |
| title_short | Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway |
| title_sort | microglia pkm2 mediates neuroinflammation and neuron loss in mice epilepsy through the astrocyte c3 neuron c3r signaling pathway |
| topic | epilepsy neural network neuroinflammation PKM2 C3 |
| url | https://www.mdpi.com/2076-3425/13/2/262 |
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