Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling
Background: Endoplasmic reticulum (ER) stress-induced nerve cell damage has been known to be a hallmark feature of Mn-induced parkinsonism pathogenesis. However, several compensatory machineries, such as unfolded protein response (UPR), autophagy, and immune response, play an essential role in this...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223018516 |
| _version_ | 1797364203140415488 |
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| author | Yuqing Yang Liang Gao Jia Meng Hong Li Xiaobai Wang Ying Huang Jie Wu Honglin Ma Dongying Yan |
| author_facet | Yuqing Yang Liang Gao Jia Meng Hong Li Xiaobai Wang Ying Huang Jie Wu Honglin Ma Dongying Yan |
| author_sort | Yuqing Yang |
| collection | DOAJ |
| description | Background: Endoplasmic reticulum (ER) stress-induced nerve cell damage has been known to be a hallmark feature of Mn-induced parkinsonism pathogenesis. However, several compensatory machineries, such as unfolded protein response (UPR), autophagy, and immune response, play an essential role in this damage, and the underlying molecular mechanisms are poorly understood. Methods: Neurobehavioral impairment was assessed using catwalk gait analysis and open field test. RNA-seq analyzed the differentially expressed genes (DEGs). TUNEL staining and immunohistochemical analysis evaluated the nerve cells apoptosis and microglial cell activation. Flow cytometry assay measured microglia M1/M2 polarization. Western blotting measured protein expression. Immunofluorescence staining was used to observe the target molecules' subcellular localization. Results: The study revealed that Mn caused a reduction in motor capacity, nerve cell apoptosis, and microglia activation with an imbalance in M1/M2 polarization, coupled with NF-κB signaling and PERK signaling activation. 4-PBA pretreatment could counteract these effects, while 3-MA administration exacerbated them. Additionally, autophagy could be activated by Mn. This activation could be further upregulated by 4-PBA pretreatment, whereas it was suppressed under 3-MA administration. Mn also decreased inactive GSK-3β, increased STAT3 signaling activation, and increased colocalization of GSK-3β and STAT3. These effects were strengthened by 4-PBA pretreatment, while 3-MA administration reversed them. Discussion: This study suggests that autophagy and M2 microglia polarization might be protective in Mn-induced ER stress damage, possibly through GSK-3β-ULK1 autophagy signaling and STAT3 signaling activation. |
| first_indexed | 2024-03-08T16:32:53Z |
| format | Article |
| id | doaj.art-0c3bc02807314b97917e0add03af4ccb |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-08T16:32:53Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-0c3bc02807314b97917e0add03af4ccb2024-01-06T04:38:05ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-01-01170116053Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signalingYuqing Yang0Liang Gao1Jia Meng2Hong Li3Xiaobai Wang4Ying Huang5Jie Wu6Honglin Ma7Dongying Yan8School of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China; Collaborative innovation center for health promotion of children and adolescents of Jinzhou Medical University, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China; Collaborative innovation center for health promotion of children and adolescents of Jinzhou Medical University, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China; Collaborative innovation center for health promotion of children and adolescents of Jinzhou Medical University, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, ChinaSchool of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China; Collaborative innovation center for health promotion of children and adolescents of Jinzhou Medical University, China; Corresponding author at: School of Public Health, Jinzhou Medical University, Section III, Linghe District, Jinzhou, China.Background: Endoplasmic reticulum (ER) stress-induced nerve cell damage has been known to be a hallmark feature of Mn-induced parkinsonism pathogenesis. However, several compensatory machineries, such as unfolded protein response (UPR), autophagy, and immune response, play an essential role in this damage, and the underlying molecular mechanisms are poorly understood. Methods: Neurobehavioral impairment was assessed using catwalk gait analysis and open field test. RNA-seq analyzed the differentially expressed genes (DEGs). TUNEL staining and immunohistochemical analysis evaluated the nerve cells apoptosis and microglial cell activation. Flow cytometry assay measured microglia M1/M2 polarization. Western blotting measured protein expression. Immunofluorescence staining was used to observe the target molecules' subcellular localization. Results: The study revealed that Mn caused a reduction in motor capacity, nerve cell apoptosis, and microglia activation with an imbalance in M1/M2 polarization, coupled with NF-κB signaling and PERK signaling activation. 4-PBA pretreatment could counteract these effects, while 3-MA administration exacerbated them. Additionally, autophagy could be activated by Mn. This activation could be further upregulated by 4-PBA pretreatment, whereas it was suppressed under 3-MA administration. Mn also decreased inactive GSK-3β, increased STAT3 signaling activation, and increased colocalization of GSK-3β and STAT3. These effects were strengthened by 4-PBA pretreatment, while 3-MA administration reversed them. Discussion: This study suggests that autophagy and M2 microglia polarization might be protective in Mn-induced ER stress damage, possibly through GSK-3β-ULK1 autophagy signaling and STAT3 signaling activation.http://www.sciencedirect.com/science/article/pii/S0753332223018516ManganeseParkinsonismER stressAutophagyMicroglia polarizationGSK-3β |
| spellingShingle | Yuqing Yang Liang Gao Jia Meng Hong Li Xiaobai Wang Ying Huang Jie Wu Honglin Ma Dongying Yan Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling Biomedicine & Pharmacotherapy Manganese Parkinsonism ER stress Autophagy Microglia polarization GSK-3β |
| title | Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling |
| title_full | Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling |
| title_fullStr | Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling |
| title_full_unstemmed | Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling |
| title_short | Manganese activates autophagy and microglia M2 polarization against endoplasmic reticulum stress-induced neuroinflammation: Involvement of GSK-3β signaling |
| title_sort | manganese activates autophagy and microglia m2 polarization against endoplasmic reticulum stress induced neuroinflammation involvement of gsk 3β signaling |
| topic | Manganese Parkinsonism ER stress Autophagy Microglia polarization GSK-3β |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223018516 |
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