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The inflammatory effects of UDP-glucose in N9 microglia are not mediated by P2Y14 receptor activation
Vielska M Brautigam1, George R Dubyak, Jessica M Crain
1Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Dr., Madison, WI, 53706, USA.
Abstract:
In this study we evaluated the functionality and inflammatory effects of P2Y14 receptors in murine N9 microglia. The selective P2Y14 receptor agonist UDP-glucose (UDPG) derived from microbial sources dose dependently stimulated expression of cyclooxygenase-2 and inducible nitric oxide synthase, and potentiated the effects of bacterial lipopolysaccharide on nitric oxide production. However, another selective P2Y14 receptor agonist, UDP-galactose, did not affect these endpoints either alone or in combination with lipopolysaccharide. Interestingly, synthetic UDPG also had no detectable pro-inflammatory effects, although P2Y14 receptors are both expressed and functional in N9 microglia. While synthetic UDPG decreased levels of phosphorylated cyclic AMP response element binding protein, an effect that was blocked by pertussis toxin, the pro-inflammatory effects of microbial-derived UDPG were insensitive to pertussis toxin. These data suggest that the pro-inflammatory effects of microbial-derived UDPG are independent of P2Y14 receptors and imply that microbial-derived contaminants in the UDPG preparation may be involved in the observed inflammatory effects.
Insights
Microbial-derived UDP-glucose (UDPG) triggers inflammation in N9 microglia, but not via P2Y14 receptors. Synthetic UDPG lacks these effects, suggesting contaminants in microbial preparations drive inflammation.
Area of Science:
- Neuroimmunology
- Molecular Pharmacology
Background:
- P2Y14 receptors are expressed on microglia and implicated in inflammatory responses.
- The role of specific P2Y14 receptor agonists, like UDP-glucose (UDPG), in microglial activation requires further elucidation.
Purpose of the Study:
- To investigate the pro-inflammatory effects of UDP-glucose (UDPG) and UDP-galactose on N9 microglia.
- To determine if these effects are mediated through P2Y14 receptors.
Main Methods:
- N9 microglia were treated with selective P2Y14 receptor agonists (microbial and synthetic UDPG, UDP-galactose) and bacterial lipopolysaccharide.
- Inflammatory markers including cyclooxygenase-2, inducible nitric oxide synthase, and nitric oxide production were measured.
- Phosphorylated cyclic AMP response element binding protein levels and pertussis toxin sensitivity were assessed.
Main Results:
- Microbial-derived UDP-glucose (UDPG) dose-dependently increased cyclooxygenase-2 and inducible nitric oxide synthase expression and potentiated lipopolysaccharide-induced nitric oxide production.
- UDP-galactose and synthetic UDPG did not elicit pro-inflammatory effects.
- Pro-inflammatory effects of microbial UDPG were pertussis toxin-insensitive, unlike the effects of synthetic UDPG on phosphorylated cyclic AMP response element binding protein.
Conclusions:
- The pro-inflammatory effects observed with microbial-derived UDP-glucose (UDPG) in N9 microglia are independent of P2Y14 receptor activation.
- Contaminants within microbial UDPG preparations likely contribute to the observed inflammatory responses, rather than UDPG itself acting through P2Y14 receptors.
