Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice
Abstract Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How in...
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| Format: | Article |
| Language: | English |
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BMC
2021-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-021-02280-2 |
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| author | Stefan Milde Francesca W. van Tartwijk Anna Vilalta Tamara C. Hornik Jacob M. Dundee Mar Puigdellívol Guy C. Brown |
| author_facet | Stefan Milde Francesca W. van Tartwijk Anna Vilalta Tamara C. Hornik Jacob M. Dundee Mar Puigdellívol Guy C. Brown |
| author_sort | Stefan Milde |
| collection | DOAJ |
| description | Abstract Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y6 receptor. We investigated here whether the P2Y6 receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the substantia nigra of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson’s disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y6 receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y6 receptor, and LPS-induced neuronal loss was reduced in mixed glial–neuronal cultures from P2Y6 receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y6 receptor, suggesting that P2Y6 receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson’s disease and other brain pathologies involving inflammatory neuronal loss. |
| first_indexed | 2024-12-20T05:48:02Z |
| format | Article |
| id | doaj.art-890f380a8f9344229c6b9ea73e367087 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T05:48:02Z |
| publishDate | 2021-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-890f380a8f9344229c6b9ea73e3670872022-12-21T19:51:16ZengBMCJournal of Neuroinflammation1742-20942021-10-011811910.1186/s12974-021-02280-2Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in miceStefan Milde0Francesca W. van Tartwijk1Anna Vilalta2Tamara C. Hornik3Jacob M. Dundee4Mar Puigdellívol5Guy C. Brown6Department of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeAbstract Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson’s disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y6 receptor. We investigated here whether the P2Y6 receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the substantia nigra of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson’s disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y6 receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y6 receptor, and LPS-induced neuronal loss was reduced in mixed glial–neuronal cultures from P2Y6 receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y6 receptor, suggesting that P2Y6 receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson’s disease and other brain pathologies involving inflammatory neuronal loss.https://doi.org/10.1186/s12974-021-02280-2MicrogliaPhagocytosisNeuroinflammationCell deathParkinson’s diseaseNeurodegeneration |
| spellingShingle | Stefan Milde Francesca W. van Tartwijk Anna Vilalta Tamara C. Hornik Jacob M. Dundee Mar Puigdellívol Guy C. Brown Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice Journal of Neuroinflammation Microglia Phagocytosis Neuroinflammation Cell death Parkinson’s disease Neurodegeneration |
| title | Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice |
| title_full | Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice |
| title_fullStr | Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice |
| title_full_unstemmed | Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice |
| title_short | Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6 receptor in mice |
| title_sort | inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the p2y6 receptor in mice |
| topic | Microglia Phagocytosis Neuroinflammation Cell death Parkinson’s disease Neurodegeneration |
| url | https://doi.org/10.1186/s12974-021-02280-2 |
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