Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y<sub>6</sub> receptor in mice.
van Tartwijk, Francesca W
Hornik, Tamara C
Dundee, Jacob M
Journal of neuroinflammation
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Milde, S., van Tartwijk, F. W., Vilalta, A., Hornik, T. C., Dundee, J. M., Puigdellívol, M., & Brown, G. C. (2021). Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y<sub>6</sub> receptor in mice.. Journal of neuroinflammation, 18 (1) https://doi.org/10.1186/s12974-021-02280-2
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 P2Y<sub>6</sub> receptor. We investigated here whether the P2Y<sub>6</sub> 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 P2Y<sub>6</sub> receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y<sub>6</sub> receptor, and LPS-induced neuronal loss was reduced in mixed glial-neuronal cultures from P2Y<sub>6</sub> receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y<sub>6</sub> receptor, suggesting that P2Y<sub>6</sub> receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson's disease and other brain pathologies involving inflammatory neuronal loss.
Phagocytosis, Cell death, Neurodegeneration, Microglia, neuroinflammation, Parkinson’s Disease, Phagoptosis, P2y6r
medical research council (MR/L010593)
Medical Research Council (MR/L010593)
innovative medicines initiative (115976)
External DOI: https://doi.org/10.1186/s12974-021-02280-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330790
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/