Astrocyte-Mediated Ischemic Tolerance
Astrocyte-Mediated Ischemic Tolerance
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DOI：
10.1523/jneurosci.4218-14.2015
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发表时间：
2015-03-04
影响因子：
5.3
通讯作者：
Koizumi, Schuichi
中科院分区：
文献类型：
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作者：
Hirayama, Yuri;Ikeda-Matsuo, Yuri;Koizumi, Schuichi
使用先前的亚致死性缺血性损伤进行预处理（PC）是通过诱导大脑缺血耐受来保护神经元的一种有吸引力的策略。尽管潜在的分子机制已被广泛研究，但几乎所有研究都集中在神经元上。在这里，我们使用小鼠大脑中动脉闭塞模型，表明星形胶质细胞在诱导脑缺血耐受中发挥着重要作用。 PC 引起神经胶质细胞的激活，但没有产生任何明显的脑损伤。星形胶质细胞而非小胶质细胞激活的时空模式与缺血耐受性密切相关。有趣的是，星形胶质细胞中的这种激活至少持续了 8 周。重要的是，用氟柠檬酸盐抑制星形胶质细胞消除了缺血耐受的诱导。为了研究其潜在机制，我们重点关注 P2X7 受体作为星形胶质细胞介导的缺血耐受的关键分子。 P2X7 受体在活化的星形胶质细胞中显着上调。 PC 诱导的缺血耐受在 P2X7 受体敲除小鼠中被消除。此外，我们的结果表明缺氧诱导因子 1 α（众所周知的缺血耐受介质）参与 P2X7 受体介导的缺血耐受。与之前侧重于神经元机制的报道不同，我们的结果表明星形胶质细胞在诱导缺血耐受中发挥着不可或缺的作用，并且星形胶质细胞中 P2X7 受体的上调至关重要。
Preconditioning (PC) using a preceding sublethal ischemic insult is an attractive strategy for protecting neurons by inducing ischemic tolerance in the brain. Although the underlying molecular mechanisms have been extensively studied, almost all studies have focused on neurons. Here, using a middle cerebral artery occlusion model in mice, we show that astrocytes play an essential role in the induction of brain ischemic tolerance. PC caused activation of glial cells without producing any noticeable brain damage. The spatiotemporal pattern of astrocytic, but not microglial, activation correlated well with that of ischemic tolerance. Interestingly, such activation in astrocytes lasted at least 8 weeks. Importantly, inhibiting astrocytes with fluorocitrate abolished the induction of ischemic tolerance. To investigate the underlying mechanisms, we focused on the P2X7 receptor as a key molecule in astrocyte-mediated ischemic tolerance. P2X7 receptors were dramatically upregulated in activated astrocytes. PC-induced ischemic tolerance was abolished in P2X7 receptor knock-out mice. Moreover, our results suggest that hypoxia-inducible factor-1 alpha, a well known mediator of ischemic tolerance, is involved in P2X7 receptor-mediated ischemic tolerance. Unlike previous reports focusing on neuron-based mechanisms, our results show that astrocytes play indispensable roles in inducing ischemic tolerance, and that upregulation of P2X7 receptors in astrocytes is essential.