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Prion infection correlates with hypersensitivity of P2X7 nucleotide receptor in a mouse microglial cell line
Takato Takenouchi1, Yoshifumi Iwamaru, Morikazu Imamura
1Transgenic Animal Research Center, National Institute of Agrobiological Sciences, Ohwashi 1-2, Tsukuba, Ibaraki 305-8634, Japan.
Abstract:
We recently established mouse microglial cells persistently infected with mouse-adapted scrapie ME7 (ScMG20/ME7) for in vitro study of prion pathogenesis. Here, we found that ScMG20/ME7 cells were hypersensitive to P2X7 receptor agonists, as demonstrated by sustained Ca(2+) influx, membrane pore formation, cell death, and interleukin-1beta release. P2X7 mRNA expression was upregulated in these cells, and also in scrapie-infected mice brains. Treatment with pentosan polysulfate eliminated the infectivity and disease-related forms of prion protein from ScMG20/ME7 cell cultures, however, hypersensitivity of P2X7 receptors remained. These results suggest that prion infections may strongly affect the P2X7 receptor system in mouse microglial cells.
Insights
Prion infection in mouse microglial cells causes P2X7 receptor hypersensitivity, leading to cell damage and inflammation. This P2X7 receptor system alteration persists even after prion infectivity is cleared.
Area of Science:
- Neuroimmunology
- Prion Disease Research
- Cellular Pathogenesis
Background:
- Microglial cells are key immune cells in the brain, implicated in prion pathogenesis.
- Prion diseases, like scrapie, involve the accumulation of misfolded prion proteins.
- The P2X7 receptor is a critical component of innate immunity and inflammation.
Purpose of the Study:
- To investigate the impact of persistent prion infection on mouse microglial cells.
- To examine the function and expression of the P2X7 receptor in prion-infected microglial cells.
- To assess the effect of pentosan polysulfate treatment on prion infectivity and P2X7 receptor activity.
Main Methods:
- Established persistently scrapie-infected mouse microglial cell cultures (ScMG20/ME7).
- Assessed P2X7 receptor function via calcium influx, membrane permeability, cell death assays, and IL-1beta release.
- Quantified P2X7 mRNA expression in infected cells and scrapie-infected mouse brains.
- Treated infected cells with pentosan polysulfate and evaluated prion infectivity and P2X7 receptor sensitivity.
Main Results:
- ScMG20/ME7 cells exhibited P2X7 receptor hypersensitivity, characterized by increased Ca(2+) influx, pore formation, cell death, and IL-1beta release.
- P2X7 mRNA levels were upregulated in infected cells and in the brains of scrapie-infected mice.
- Pentosan polysulfate treatment eradicated prion infectivity and disease-related prion protein but did not reverse P2X7 receptor hypersensitivity.
Conclusions:
- Prion infection induces significant alterations in the P2X7 receptor system of mouse microglial cells.
- The observed P2X7 receptor hypersensitivity may contribute to neuroinflammation in prion diseases.
- Targeting the P2X7 receptor pathway could be a potential therapeutic strategy for prion diseases, although its persistent activation warrants further investigation.
