title: Astrocytes protect neurons against methylmercury via ATP/P2Y(1) receptor-mediated pathways in astrocytes.
abstract: Methylmercury (MeHg) is a well known environmental pollutant that induces serious neuronal damage. Although MeHg readily crosses the blood-brain barrier, and should affect both neurons and glial cells, how it affects glia or neuron-to-glia interactions has received only limited attention. Here, we report that MeHg triggers ATP/P2Y1 receptor signals in astrocytes, thereby protecting neurons against MeHg via interleukin-6 (IL-6)-mediated pathways. MeHg increased several mRNAs in astrocytes, among which IL-6 was the highest. For this, ATP/P2Y1 receptor-mediated mechanisms were required because the IL-6 production was (i) inhibited by a P2Y1 receptor antagonist, MRS2179, (ii) abolished in astrocytes obtained from P2Y1 receptor-knockout mice, and (iii) mimicked by exogenously applied ATP. In addition, (iv) MeHg released ATP by exocytosis from astrocytes. As for the intracellular mechanisms responsible for IL-6 production, p38 MAP kinase was involved. MeHg-treated astrocyte-conditioned medium (ACM) showed neuro-protective effects against MeHg, which was blocked by anti-IL-6 antibody and was mimicked by the application of recombinant IL-6. As for the mechanism of neuro-protection by IL-6, an adenosine A1 receptor-mediated pathway in neurons seems to be involved. Taken together, when astrocytes sense MeHg, they release ATP that autostimulates P2Y1 receptors to upregulate IL-6, thereby leading to A1 receptor-mediated neuro-protection against MeHg.
authors.affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Fujishita
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Imura
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Morizawa
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D015850:Interleukin-6; D008767:Methylmercury Compounds; D043682:Receptor, Adenosine A1; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases