Different danger signals differently impact on microglial proliferation through alterations of ATP release and extracellular metabolism

Abstract

Microglia rely on their ability to proliferate in the brain parenchyma to sustain brain innate immunity and participate in the reaction to brain damage. We now studied the influence of different danger signals activating microglia, both internal (typified by glutamate, associated with brain damage) and external (using a bacterial lipopolysaccharide, LPS), on the proliferation of microglia cells. We found that LPS (100 ng/mL) increased, whereas glutamate (0.5 mM) decreased proliferation. Notably, LPS decreased whereas glutamate increased the extracellular levels of ATP. In contrast, LPS increased whereas glutamate decreased the extracellular catabolism of ATP into adenosine through ecto-nucleotidases and ecto-5'-nucleotidase. Finally, apyrase (degrades extracellular ATP) abrogated glutamate-induced inhibition of microglia proliferation; conversely, inhibitors of ecto-nucleotidases (ARL67156 or α,β-methylene ADP) and adenosine deaminase (degrades extracellular adenosine) abrogated the LPS-induced increase of microglia proliferation, which was blocked by a selective A2A receptor antagonist, SCH58261 (50 nM). Overall, these results highlight the importance of the extracellular purinergic metabolism to format microglia proliferation and influence the spatio-temporal profile of neuroinflammation in different conditions of brain damage.

Disruption of theATP/adenosine balance inCD39−/−mice is associated with handling‐induced seizures

“…This is consistent with the finding that microglia have no effect on epileptogenesis in hippocampal cultures . However, our results are inconsistent with reports showing that ATP and adenosine affect microglia activation and migration . Matyash et al .…”

Role of purinergic signaling in experimental pneumococcal meningitis

“…This rise was undetectable in the presence of BMN or BMDM, but (at least in part) reversible by the co-administration of ARL67156. Thus, our findings are in line with that of George and colleagues46, and suggest a contribution of CD39 to the meningitis-associated decrease in CSF ATP.…”

“…Recently, George and colleagues46 demonstrated that E. coli LPS can increase the extracellular catabolism of ATP into adenosine through ectonucleotidases by cultured microglial cells. In order to evaluate whether locally present immune cells contribute to the drop of CSF ATP levels in PM, we next cultured live S. pneumoniae in the absence or presence of murine BMN or BMDM in aCSF to which ATP was added at its physiological concentration24.…”

N-acetylcysteine attenuates lipopolysaccharide-induced impairment in lamination of Ctip2-and Tbr1- expressing cortical neurons in the developing rat fetal brain

“…We found no significant difference in the percentage of subventricular/ventricular zone at GD18, but did notice an effect at GD20, which may be related to LPS-induced gliosis or migration failure as discussed below. The alteration of cortex or cortical plate thickness may be due to the initial proliferation and activation of microglia, which subsequently decreases or returns to normal1256. Indeed, we found that microglia are activated in the presence of LPS (Fig.…”