Melatonin Suppresses Microglial Necroptosis by Regulating Deubiquitinating Enzyme A20 After Intracerebral Hemorrhage
Melatonin Suppresses Microglial Necroptosis by Regulating Deubiquitinating Enzyme A20 After Intracerebral Hemorrhage
复制标题
褪黑素通过调节脑出血后去泛素化酶 A20 抑制小胶质细胞坏死性凋亡
DOI：
10.3389/fimmu.2019.01360
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发表时间：
2019-06-14
影响因子：
7.3
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
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作者：
Lu, Jianan;Sun, Zeyu;Zhang, Jianmin
细胞死亡是脑出血后脑损伤的病理生理学基础。坏死性凋亡是最近发现的细胞死亡形式之一，在包括ICH在内的各种疾病中起着重要作用。以往的研究表明，脑出血后相当数量的神经元发生坏死性凋亡。然而，脑出血后小胶质细胞坏死性凋亡至今未见报道。本研究首次证明，在C57小鼠脑出血后血肿周围的小胶质细胞中发生坏死性凋亡，褪黑激素（一种主要在松果体中合成和分泌的激素）通过抑制这一过程发挥神经保护作用。当我们进一步探索潜在的潜在机制时，我们发现褪黑激素通过调节脑出血后去泛素化酶A20（也称为TNFAIP3）的表达来抑制RIP3介导的坏死性凋亡。总之，我们已经证实了小胶质细胞坏死性凋亡在脑出血发病机制中的作用。更重要的是，A20被确定为褪黑激素的新靶点，这为未来的研究开辟了前景。
Cell death is deeply involved in pathophysiology of brain injury after intracerebral hemorrhage (ICH). Necroptosis, one of the recently discovered forms of cell death, plays an important role in various diseases, including ICH. Previous studies have suggested that a considerable number of neurons undergoes necroptosis after ICH. However, necroptosis of microglia after ICH has not been reported to date. The present study demonstrated for the first time that necroptosis occurred in the microglia surrounding the hematoma after ICH in C57 mice, and melatonin, a hormone that is predominantly synthesized in and secreted from the pineal gland, exerted a neuroprotective effect by suppressing this process. When we further explored the potential underlying mechanism, we found that melatonin inhibits RIP3-mediated necroptosis by regulating the deubiquitinating enzyme A20 (also known as TNFAIP3) expression after ICH. In summary, we have demonstrated the role of microglial necroptosis in the pathogenesis of ICH. More importantly, A20 was identified as a novel target of melatonin, which opens perspectives for future research.