Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway
Trpm2 deficiency in microglia attenuates neuroinflammation during epileptogenesis by upregulating autophagy via the AMPK/mTOR pathway
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DOI：
10.1016/j.nbd.2023.106273
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发表时间：
2023-08
影响因子：
6.1
通讯作者：
Cheng Chen;Tao Zhu;Lifen Gong;Zhe Hu;Hao Wei;Jian-wei Fan;D. Lin;Xiaojun Wang;Junyu Xu
中科院分区：
文献类型：
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作者：
Cheng Chen;Tao Zhu;Lifen Gong;Zhe Hu;Hao Wei;Jian-wei Fan;D. Lin;Xiaojun Wang;Junyu Xu
癫痫是最常见的神经系统疾病之一。涉及小胶质细胞和星形胶质细胞激活的神经炎症是癫痫发生的一个重要而常见的机制。瞬时受体电位美拉他汀2 （TRPM2）是一种钙渗透性非选择性阳离子通道，在多种炎症相关疾病中起病理作用。我们之前的研究表明，敲除attrpm2对匹罗卡品诱导的神经胶质激活和神经炎症具有治疗作用。然而，小胶质细胞和星形胶质细胞中的TRPM2是否在这一过程中发挥共同的致病作用及其潜在的分子机制尚不清楚。在这里，我们证明了以前未知的小胶质细胞TRPM2在癫痫发生中的作用。在小胶质细胞中敲除trpm2可减弱kainic酸（KA）诱导的胶质细胞激活、炎症细胞因子产生和海马发作性放电，而在星形胶质细胞中敲除astrpm2无显著影响。此外，我们发现这些治疗效果是由小胶质细胞中上调的自噬-腺苷单磷酸活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶蛋白（mTOR）途径介导的。因此，我们的研究结果强调了小胶质细胞TRPM2在颞叶癫痫中的重要有害作用。
Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated thatTrpm2knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis.Trpm2knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereasTrpm2knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagyviathe adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.