Thermosensitive TRPV4 channels mediate temperature-dependent microglia movement.
Thermosensitive TRPV4 channels mediate temperature-dependent microglia movement.
复制标题
温度敏感性TRPV4通道介导温度依赖性小胶质细胞运动。
DOI：
10.1073/pnas.2012894118
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发表时间：
2021-04-27
影响因子：
11.1
通讯作者：
Tominaga M
中科院分区：
文献类型：
--
作者：
Nishimoto R;Derouiche S;Eto K;Deveci A;Kashio M;Kimori Y;Matsuoka Y;Morimatsu H;Nabekura J;Tominaga M
运动是小胶质细胞监视和保护作用的一个关键特征。这种动态过程受到周围环境的高度调节。我们发现，在体外和体内的小胶质细胞的运动是温度依赖性的。我们对热敏TRP通道参与这一现象的研究揭示了几个候选者，包括TRPM 2，TRPM 4和TRPV 4通道。使用药理学工具和转基因小鼠，我们发现小胶质细胞运动的温度依赖性主要依赖于TRPV4通道活性。了解温度调节小胶质细胞运动的机制将提高我们对病理过程的理解，并允许识别用于治疗脑病理的新线索。小胶质细胞通过监测其环境的变化（静息状态）和通过采取保护性行动来平衡这种变化（激活状态）来维持中枢神经系统的稳态。这些监视和保护作用都需要小胶质细胞的持续运动。有趣的是，诱导低温可以减少缺血引起的小胶质细胞迁移，表明小胶质细胞的运动可以通过温度调节。虽然已知几种离子通道和转运蛋白支持小胶质细胞运动，但调节小胶质细胞温度依赖性运动的精确分子机制仍不清楚。瞬时受体电位（TRP）通道超家族的一些成员表现出热敏性，因此是介导这种现象的强有力的候选者。在这里，我们证明了小鼠小胶质细胞在体外和体内表现出温度依赖性运动，这是由TRPV4通道介导的生理体温范围内。我们的研究结果可能为未来的研究提供了基础，通过操纵离子通道活性来调节温度以保护细胞功能的潜在临床应用。
Movement is a key feature of the surveillance and protective roles of microglia. This dynamic process is highly modulated by the surrounding environment. We discovered that microglia movement is temperature dependent in vitro and in vivo. Our investigation of thermosensitive TRP channel involvement in this phenomenon revealed several candidates including TRPM2, TRPM4, and TRPV4 channels. Using pharmacological tools and transgenic mice, we showed that the temperature dependency of microglia movement mainly relies on TRPV4 channel activity. Understanding the mechanisms by which temperature modulates microglia movement will improve our comprehension of pathological processes and allow the identification of new leads for the treatment of brain pathologies. Microglia maintain central nervous system homeostasis by monitoring changes in their environment (resting state) and by taking protective actions to equilibrate such changes (activated state). These surveillance and protective roles both require constant movement of microglia. Interestingly, induced hypothermia can reduce microglia migration caused by ischemia, suggesting that microglia movement can be modulated by temperature. Although several ion channels and transporters are known to support microglia movement, the precise molecular mechanism that regulates temperature-dependent movement of microglia remains unclear. Some members of the transient receptor potential (TRP) channel superfamily exhibit thermosensitivity and thus are strong candidates for mediation of this phenomenon. Here, we demonstrate that mouse microglia exhibit temperature-dependent movement in vitro and in vivo that is mediated by TRPV4 channels within the physiological range of body temperature. Our findings may provide a basis for future research into the potential clinical application of temperature regulation to preserve cell function via manipulation of ion channel activity.
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