Microglia trigger astrocyte-mediated neuroprotection via purinergic gliotransmission.
Microglia are highly sensitive to even small changes in the brain environment, such as invasion of non-hazardous toxicants or the presymptomatic state of diseases. However, the physiological or pathophysiological consequences of their responses remain unknown. Here, we report that cultured microglia sense low concentrations of the neurotoxicant methylmercury (MeHg(low)) and provide neuroprotection against MeHg, for which astrocytes are also required. When exposed to MeHg(low), microglia exocytosed ATP via p38 MAPK- and vesicular nucleotide transporter (VNUT)-dependent mechanisms. Astrocytes responded to the microglia-derived ATP via P2Y1 receptors and released interleukin-6 (IL-6), thereby protecting neurons against MeHg(low). These neuroprotective actions were also observed in organotypic hippocampal slices from wild-type mice, but not in slices prepared from VNUT knockout or P2Y1 receptor knockout mice. These findings suggest that microglia sense and respond to even non-hazardous toxicants such as MeHg(low) and change their phenotype into a neuroprotective one, for which astrocytic support is required.
1] Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
Youichi
Y
Shinozaki
Department of Endocrine and Metabolic Diseases/Diabetes Mellitus Kyushu University Hospital, Fukuoka 812-8582, Japan.
Masatoshi
M
Nomura
Institute for Innovation, Ajinomoto Co. Inc., Kawasaki 210-8681, Japan.
Ken
K
Iwatsuki
Advanced Science Research Center, Okayama University, Okayama 700-8530, Japan.
Yoshinori
Y
Moriyama
Institut National de la Santé et de la Recherche Médicale (INSERM), U.311, Etablissement de Transfusion Sanguine, 10, rue Spielmann, B.P. 36, 67065 Strasbourg, France.
Christian
C
Gachet
1] Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0076, Japan.
Schuichi
S
Koizumi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D020013:Calcium Signaling; D002450:Cell Communication; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008767:Methylmercury Compounds / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D033704:Nucleotide Transport Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015850:Interleukin-6; D008767:Methylmercury Compounds; D033704:Nucleotide Transport Proteins; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases