Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model
Lu Jing,1,2,* Liyan Hou,1,* Dongdong Zhang,1 Sheng Li,3 Zhengzheng Ruan,1 Xiaomeng Zhang,3 Jau-Shyong Hong,4 Qingshan Wang1,3 1Institute of Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Neurology, The First Affili...
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Dove Medical Press
2021
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pesticide noradrenergic neuron parkinson’s disease neuroinflammation cr3 locus coeruleus Pathology RB1-214 Therapeutics. Pharmacology RM1-950 |
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pesticide noradrenergic neuron parkinson’s disease neuroinflammation cr3 locus coeruleus Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Jing L Hou L Zhang D Li S Ruan Z Zhang X Hong JS Wang Q Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
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Lu Jing,1,2,* Liyan Hou,1,* Dongdong Zhang,1 Sheng Li,3 Zhengzheng Ruan,1 Xiaomeng Zhang,3 Jau-Shyong Hong,4 Qingshan Wang1,3 1Institute of Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China; 3National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, People’s Republic of China; 4Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA*These authors contributed equally to this workCorrespondence: Qingshan WangInstitute of Toxicology, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, People’s Republic of ChinaTel +86 138 4081 7365Email wangq4@126.comBackground: Chronic exposure to the insecticide rotenone can damage dopaminergic neurons and lead to an increased risk of Parkinson’s disease (PD). Whereas it is not clear whether rotenone induces neurodegeneration of noradrenergic locus coeruleus (LC/NE) neurons. Chronic neuroinflammation mediated by microglia has been involved in the pathogenesis of PD. Evidence shows that complement receptor 3 (CR3) is a crucial regulator of microglial activation and related neurodegeneration. However, it is not clear whether CR3 mediates rotenone-elicited degeneration of LC/NE neurons through microglia-mediated neuroinflammation.Materials and Methods: Wild type (WT) and CR3 knockout (KO) mice were treated with rotenone. PLX3397 and minocycline were used to deplete or inactivate the microglia. Leukadherin-1 (LA-1) was used to modulate CR3. LC/NE neurodegeneration, microglial phenotype, and expression of CR3 were determined by using immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) techniques. The glutathione (GSH) and malondialdehyde (MDA) contents were measured by using commercial kits.Results: Rotenone exposure led to dose- and time-dependent LC/NE neuronal loss and microglial activation in mice. Depletion of microglia by PLX3397 or inhibition of microglial activation by minocycline significantly reduced rotenone-induced LC/NE neurodegeneration. Mechanistic studies revealed that CR3 played an essential role in the rotenone-induced activation of microglia and neurodegeneration of LC/NE neurons. Rotenone elevated the expression of CR3, and genetic ablation of CR3 markedly reduced rotenone-induced microglial activation and M1 polarization. LA-1 also suppressed rotenone-induced toxic microglial M1 activation. Furthermore, lack of CR3 or treatment with LA-1 reduced oxidative stress in the brainstem of rotenone-intoxicated mice. Finally, we found that mice deficient in CR3 or treated with LA-1 were more resistant to rotenone-induced LC/NE neurodegeneration than WT or vehicle-treated mice, respectively.Conclusion: Our results indicate that CR3-mediated microglial activation participates in rotenone-induced LC/NE neurodegeneration, providing novel insight into environmental toxin-induced neurotoxicity and related Parkinsonism.Keywords: pesticide, noradrenergic neuron, Parkinson’s disease, neuroinflammation, CR3, locus coeruleus |
| format |
article |
| author |
Jing L Hou L Zhang D Li S Ruan Z Zhang X Hong JS Wang Q |
| author_facet |
Jing L Hou L Zhang D Li S Ruan Z Zhang X Hong JS Wang Q |
| author_sort |
Jing L |
| title |
Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
| title_short |
Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
| title_full |
Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
| title_fullStr |
Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
| title_full_unstemmed |
Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model |
| title_sort |
microglial activation mediates noradrenergic locus coeruleus neurodegeneration via complement receptor 3 in a rotenone-induced parkinson’s disease mouse model |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/088e566a3d67466995605b7a305ce0b2 |
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oai:doaj.org-article:088e566a3d67466995605b7a305ce0b22021-12-02T18:15:38ZMicroglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model1178-7031https://doaj.org/article/088e566a3d67466995605b7a305ce0b22021-04-01T00:00:00Zhttps://www.dovepress.com/microglial-activation-mediates-noradrenergic-locus-coeruleus-neurodege-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Lu Jing,1,2,* Liyan Hou,1,* Dongdong Zhang,1 Sheng Li,3 Zhengzheng Ruan,1 Xiaomeng Zhang,3 Jau-Shyong Hong,4 Qingshan Wang1,3 1Institute of Toxicology, School of Public Health, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China; 3National-Local Joint Engineering Research Center for Drug-Research and Development (R & D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, People’s Republic of China; 4Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA*These authors contributed equally to this workCorrespondence: Qingshan WangInstitute of Toxicology, School of Public Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, People’s Republic of ChinaTel +86 138 4081 7365Email wangq4@126.comBackground: Chronic exposure to the insecticide rotenone can damage dopaminergic neurons and lead to an increased risk of Parkinson’s disease (PD). Whereas it is not clear whether rotenone induces neurodegeneration of noradrenergic locus coeruleus (LC/NE) neurons. Chronic neuroinflammation mediated by microglia has been involved in the pathogenesis of PD. Evidence shows that complement receptor 3 (CR3) is a crucial regulator of microglial activation and related neurodegeneration. However, it is not clear whether CR3 mediates rotenone-elicited degeneration of LC/NE neurons through microglia-mediated neuroinflammation.Materials and Methods: Wild type (WT) and CR3 knockout (KO) mice were treated with rotenone. PLX3397 and minocycline were used to deplete or inactivate the microglia. Leukadherin-1 (LA-1) was used to modulate CR3. LC/NE neurodegeneration, microglial phenotype, and expression of CR3 were determined by using immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) techniques. The glutathione (GSH) and malondialdehyde (MDA) contents were measured by using commercial kits.Results: Rotenone exposure led to dose- and time-dependent LC/NE neuronal loss and microglial activation in mice. Depletion of microglia by PLX3397 or inhibition of microglial activation by minocycline significantly reduced rotenone-induced LC/NE neurodegeneration. Mechanistic studies revealed that CR3 played an essential role in the rotenone-induced activation of microglia and neurodegeneration of LC/NE neurons. Rotenone elevated the expression of CR3, and genetic ablation of CR3 markedly reduced rotenone-induced microglial activation and M1 polarization. LA-1 also suppressed rotenone-induced toxic microglial M1 activation. Furthermore, lack of CR3 or treatment with LA-1 reduced oxidative stress in the brainstem of rotenone-intoxicated mice. Finally, we found that mice deficient in CR3 or treated with LA-1 were more resistant to rotenone-induced LC/NE neurodegeneration than WT or vehicle-treated mice, respectively.Conclusion: Our results indicate that CR3-mediated microglial activation participates in rotenone-induced LC/NE neurodegeneration, providing novel insight into environmental toxin-induced neurotoxicity and related Parkinsonism.Keywords: pesticide, noradrenergic neuron, Parkinson’s disease, neuroinflammation, CR3, locus coeruleusJing LHou LZhang DLi SRuan ZZhang XHong JSWang QDove Medical Pressarticlepesticidenoradrenergic neuronparkinson’s diseaseneuroinflammationcr3locus coeruleusPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 1341-1356 (2021) |