The Neuroprotective Effect of a Specific P2X7 Receptor Antagonist Derives from its Ability to Inhibit Assembly of the NLRP3 Inflammasome in Glial Cells
The Neuroprotective Effect of a Specific P2X7 Receptor Antagonist Derives from its Ability to Inhibit Assembly of the NLRP3 Inflammasome in Glial Cells
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DOI：
10.1111/j.1750-3639.2011.00531.x
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发表时间：
2012-05-01
期刊：
影响因子：
6.4
通讯作者：
Lynch, Marina A.
中科院分区：
文献类型：
--
作者：
Murphy, Niamh;Cowley, Thelma R.;Lynch, Marina A.
免疫活性细胞释放IL-1β需要形成Nacht、LLR和PYD结构域的含有蛋白3(NLRP3)的炎性小体，并激活caspase 1。作用于P2X7受体的三磷酸腺苷(ATP)是刺激炎症体组装的因素之一。我们发现一种新型的特异性的P2X7受体拮抗剂，GSK1370319A，通过阻断pannin 1依赖的炎症体的组装，抑制了ATP诱导的脂多糖(LPS)诱导的混合胶质细胞IL-1β释放和caspase 1激活的增加。GSK1370319A还抑制ATP诱导的海马器型脑片培养中亚区特异性神经元的丢失，这依赖于其防止神经胶质细胞中炎症性小体组装的能力。值得注意的是，GSK1370319A减轻了与年龄相关的长时程增强(LTP)缺陷，并抑制了伴随而来的与年龄相关的caspase 1活性。我们的结论是，抑制P2X7受体激活的NLRP3炎症体的形成和随后胶质细胞释放IL-1β可以保护神经元的活性和突触的活性。
Release of interleukin (IL)-1 beta from immunocompetent cells requires formation of the NACHT, LLR and PYD domains-containing protein 3 (NLRP3) inflammasome and caspase 1 activation. Adenosine 5'-triphosphate (ATP), acting on the P2X7 receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X7 receptor antagonist, GSK1370319A, inhibits ATP-induced increase in IL-1 beta release and caspase 1 activation in lipopolysaccharide (LPS)-primed mixed glia by blocking assembly of the inflammasome in a pannexin 1-dependent manner. GSK1370319A also inhibits ATP-induced subregion-specific neuronal loss in hippocampal organotypic slice cultures, which is dependent on its ability to prevent inflammasome assembly in glia. Significantly, GSK1370319A attenuates age-related deficits in long-term potentiation (LTP) and inhibits the accompanying age-related caspase 1 activity. We conclude that inhibiting P2X7 receptor-activated NLRP3 inflammasome formation and the consequent IL-1 beta release from glia preserve neuronal viability and synaptic activity.