Coordinate effects of P2X7 and extracellular acidification in microglial cells.
Coordinate effects of P2X7 and extracellular acidification in microglial cells.
复制标题
DOI：
10.18632/oncotarget.24331
复制
发表时间：
2018-02-27
期刊：
影响因子：
--
通讯作者：
Lin WW
中科院分区：
文献类型：
--
作者：
Sekar P;Huang DY;Chang SF;Lin WW
细胞外腺苷三磷酸（ATP）是一种损伤相关的分子模式，并有助于炎症相关疾病，包括癌症。细胞外酸中毒是炎症部位的一种新的危险信号，它可以调节炎症、免疫和肿瘤生长。细胞外酸化显示抑制P2 X7介导的通道电流，但酸化和P2 X7如何共同影响细胞反应仍不清楚。在这里，我们在短时间内（<15分钟）或持续酸化条件下用ATP处理BV-2小胶质细胞。对于短期酸化，我们比较了中性ATP和酸性ATP在pH缓冲条件下的作用。对于持续酸化，我们在酸性培养基中用中和的ATP或在没有pH缓冲的培养基中用酸性ATP处理细胞。在短期酸化条件下，中和ATP比酸性ATP诱导更高的细胞内钙和活性氧增加，细胞内钾减少，诱导细胞死亡。相反，这些细胞的反应和线粒体分裂所造成的中和ATP增强pH 6.0和pH 4.5的媒体。P2 X7激活也可以迅速阻断线粒体ATP周转和呼吸能力，这两者都被尼日利亚菌素模拟并被酸性增强。总之，P2 X7介导的离子通量和活性氧物质的产生在短时间酸化下减弱，而持续酸化本身可诱导线粒体毒性，其在P2 X7活化下使线粒体功能恶化。
Extracellular adenosine 5′-triphosphate (ATP) is a damage-associated molecular pattern and contributes to inflammation associated diseases including cancer. Extracellular acidosis is a novel danger signal in the inflammatory sites, where it can modulate inflammation, immunity and tumor growth. Extracellular acidification was shown to inhibit P2X7-mediated channel currents, while it remains unknown how acidification and P2X7 together affect cellular responses. Here, we treated BV-2 microglial cells with ATP in a short period (<15 min) or a sustained acidified condition. For short acidification we compared the actions of neutralized ATP and acidic ATP in a condition with pH buffering. For sustained acidification, we treated cells with neutralized ATP in acidic medium or acidic ATP in medium without pH buffering. In the short acidified condition, neutralized ATP induced higher responses than acidic ATP to increase intracellular calcium and reactive oxygen species, decrease intracellular potassium and induce cell death. In contrast, these cellular responses and mitochondrial fission caused by neutralized ATP were enhanced by pH 6.0 and pH 4.5 media. P2X7 activation can also rapidly block mitochondrial ATP turnover and respiration capacity, both of which were mimicked by nigericin and enhanced by acidity. Taken together P2X7-mediated ionic fluxes and reactive oxygen species production are attenuated under short acidification, while sustained acidification itself can induce mitochondrial toxicity which deteriorates the mitochondrial function under P2X7 activation.