title: 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.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Jimmy
authors.initials: J
authors.lastname: George
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Francisco Q
authors.initials: FQ
authors.lastname: Gonçalves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Cristóvão
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rodrigues
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal Do Rio De Janeiro, Rio De Janeiro, Brazil.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: Meyer Fernandes
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gonçalves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.|FMUC-Faculty of Medicine, University of Coimbra, Portugal.
authors.forename: Catarina A
authors.initials: CA
authors.lastname: Gomes
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001081:Apyrase / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D058917:Adenosine A2 Receptor Antagonists; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011743:Pyrimidines; D043683:Receptors, Adenosine A2; D014230:Triazoles; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D001081:Apyrase; D000241:Adenosine
keywords: A2A receptor; ATP; adenosine; microglia