A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels
A calcium-redox feedback loop controls human monocyte immune responses: The role of ORAI Ca2+ channels
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DOI：
10.1126/scisignal.aaf1639
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发表时间：
2016-03-08
影响因子：
7.3
通讯作者：
Bogeski, Ivan
中科院分区：
文献类型：
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作者：
Saul, Stephanie;Gibhardt, Christine S.;Bogeski, Ivan
在吞噬细胞中，病原体识别之后是 Ca2+ 动员和 NADPH 氧化酶 2 (NOX2) 介导的“氧化爆发”，其中涉及快速产生大量活性氧 (ROS)。我们发现 ORAI Ca2+ 通道控制原代人单核细胞中钙池操纵的 Ca2+ 进入、ROS 产生和细菌杀灭。 ROS 使缺少 ORAI3 亚基的 ORAI 通道失活。小鼠的葡萄球菌感染降低了肺部或支气管肺泡灌洗液中编码氧化还原敏感的Orai1的基因的表达，并增加了编码氧化还原不敏感的Orai3的基因的表达。在暴露于培养物中的细菌肽的原代人单核细胞中，也发生了从 ORAI1 到 ORAI3 的类似转变。 ORAI1 和 ORAI3 丰度的这些变化将通道组装转向对氧化还原更加不敏感的配置。因此，沉默 ORAI3 会增加通道的氧化还原敏感性，并增强氧化诱导的 NOX2 抑制。我们生成了一个数学模型来预测 Ca2+-氧化还原相互作用的其他特征。我们的结果确定 ORAI-NOX2 反馈环路是单核细胞免疫反应的决定因素。
In phagocytes, pathogen recognition is followed by Ca2+ mobilization and NADPH oxidase 2 (NOX2)-mediated "oxidative burst," which involves the rapid production of large amounts of reactive oxygen species (ROS). We showed that ORAI Ca2+ channels control store-operated Ca2+ entry, ROS production, and bacterial killing in primary human monocytes. ROS inactivate ORAI channels that lack an ORAI3 subunit. Staphylococcal infection of mice reduced the expression of the gene encoding the redox-sensitive Orai1 and increased the expression of the gene encoding the redox-insensitive Orai3 in the lungs or in bronchoalveolar lavages. A similar switch from ORAI1 to ORAI3 occurred in primary human monocytes exposed to bacterial peptides in culture. These alterations in ORAI1 and ORAI3 abundance shifted the channel assembly toward a more redox-insensitive configuration. Accordingly, silencing ORAI3 increased the redox sensitivity of the channel and enhanced oxidation-induced inhibition of NOX2. We generated a mathematical model that predicted additional features of the Ca2+-redox interplay. Our results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses.