Shinozaki Youichi, Nomura Masatoshi, Iwatsuki Ken, Moriyama Yoshinori, Gachet Christian, Koizumi Schuichi
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.
Department of Endocrine and Metabolic Diseases/Diabetes Mellitus Kyushu University Hospital, Fukuoka 812-8582, Japan.
Sci Rep. 2014 Mar 10;4:4329. doi: 10.1038/srep04329.
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.
小胶质细胞对大脑环境中即使很小的变化都高度敏感，例如无害毒物的侵入或疾病的症状前状态。然而，它们反应的生理或病理生理后果仍然未知。在此，我们报告培养的小胶质细胞能感知低浓度的神经毒物甲基汞（低浓度甲基汞），并对甲基汞提供神经保护作用，而这一过程也需要星形胶质细胞参与。当暴露于低浓度甲基汞时，小胶质细胞通过p38丝裂原活化蛋白激酶（p38 MAPK）和囊泡核苷酸转运体（VNUT）依赖的机制分泌ATP。星形胶质细胞通过P2Y1受体对小胶质细胞来源的ATP做出反应，并释放白细胞介素-6（IL-6），从而保护神经元免受低浓度甲基汞的损伤。在野生型小鼠的脑片培养物中也观察到了这些神经保护作用，但在从VNUT基因敲除或P2Y1受体基因敲除小鼠制备的脑片中未观察到。这些发现表明，小胶质细胞能感知并对即使是低浓度甲基汞这种无害毒物做出反应，并将其表型转变为具有神经保护作用的表型，而这需要星形胶质细胞的支持。
