Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways
Abstract Background Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-β1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02557-0 |
| _version_ | 1818018685287137280 |
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| author | Yi Xie Xuejiao Chen Ying Li Simiao Chen Shuai Liu Zhiyuan Yu Wei Wang |
| author_facet | Yi Xie Xuejiao Chen Ying Li Simiao Chen Shuai Liu Zhiyuan Yu Wei Wang |
| author_sort | Yi Xie |
| collection | DOAJ |
| description | Abstract Background Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-β1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-β1 on demyelinating diseases and its underlying mechanisms have not been well investigated. Methods A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-β1 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism. Results The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-β1. Besides, TGF-β1 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1β, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-β1. Mechanistically, TGF-β1 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1β. Activation of ERK1/2 and NF-κB pathways largely abolished the protective effects of TGF-β1, which indicated that TGF-β1 alleviated the pyroptosis possibly via regulating NF-κB/ERK1/2 signal pathways. Conclusions Our studies demonstrated TGF-β1 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1/2 and NF-κB pathways. Targeting TGF-β1 activity might serve as a promising therapeutic strategy in demyelinating diseases. |
| first_indexed | 2024-04-14T07:43:21Z |
| format | Article |
| id | doaj.art-614edac0143a4344841afcafe2d685b4 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-14T07:43:21Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-614edac0143a4344841afcafe2d685b42022-12-22T02:05:25ZengBMCJournal of Neuroinflammation1742-20942022-07-0119112010.1186/s12974-022-02557-0Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathwaysYi Xie0Xuejiao Chen1Ying Li2Simiao Chen3Shuai Liu4Zhiyuan Yu5Wei Wang6Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Rehabilitation Medicine, The First Affiliated Hospital of Medical College, Zhejiang UniversityReproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-β1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-β1 on demyelinating diseases and its underlying mechanisms have not been well investigated. Methods A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-β1 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism. Results The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-β1. Besides, TGF-β1 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1β, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-β1. Mechanistically, TGF-β1 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1β. Activation of ERK1/2 and NF-κB pathways largely abolished the protective effects of TGF-β1, which indicated that TGF-β1 alleviated the pyroptosis possibly via regulating NF-κB/ERK1/2 signal pathways. Conclusions Our studies demonstrated TGF-β1 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1/2 and NF-κB pathways. Targeting TGF-β1 activity might serve as a promising therapeutic strategy in demyelinating diseases.https://doi.org/10.1186/s12974-022-02557-0DemyelinationCognitive deficitLPCTGF-β1MicrogliaPyroptosis |
| spellingShingle | Yi Xie Xuejiao Chen Ying Li Simiao Chen Shuai Liu Zhiyuan Yu Wei Wang Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways Journal of Neuroinflammation Demyelination Cognitive deficit LPC TGF-β1 Microglia Pyroptosis |
| title | Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways |
| title_full | Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways |
| title_fullStr | Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways |
| title_full_unstemmed | Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways |
| title_short | Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways |
| title_sort | transforming growth factor β1 protects against lpc induced cognitive deficit by attenuating pyroptosis of microglia via nf κb erk1 2 pathways |
| topic | Demyelination Cognitive deficit LPC TGF-β1 Microglia Pyroptosis |
| url | https://doi.org/10.1186/s12974-022-02557-0 |
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