Continued P2X7 activation leads to mitochondrial fission and compromising microglial phagocytosis after subarachnoid haemorrhage.
Continued P2X7 activation leads to mitochondrial fission and compromising microglial phagocytosis after subarachnoid haemorrhage.
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蛛网膜下腔出血后 P2X7 持续激活导致线粒体裂变并损害小胶质细胞吞噬作用
DOI：
10.1111/jnc.15712
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发表时间：
2022-12
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
蛛网膜下腔出血（SAH）具有很高的致残率和死亡率。包括三磷酸腺苷（ATP）在内的极具破坏性的分子从外渗的红细胞和神经细胞中释放出来，激活小胶质细胞并诱导无菌组织损伤和器官功能障碍。P2X嘌呤受体7（P2X7）是小胶质细胞表面最重要的嘌呤受体之一，参与小胶质细胞的促炎激活。虽然P2X7也可以影响小胶质细胞的吞噬作用，但其机制尚不清楚。在这里，我们证明了小胶质细胞吞噬作用在持续BzATP暴露和P2X7激活下进行性受损。此外，我们发现P2X7激活导致细胞内Ca2+水平增加，并激活钙调磷酸酶，使动力蛋白相关蛋白1（DRP1）S637去磷酸化。DRP1在S637处的去磷酸化导致线粒体分裂增加和线粒体功能降低，这可能是小胶质细胞吞噬功能降低的原因。最后，我们在小鼠中抑制了P2X7的激活，这导致了线粒体功能的拯救和小胶质细胞增殖的减少，但改善了SAH后的吞噬作用。我们的研究证实了SAH后P2X7激活通过线粒体分裂导致小胶质细胞吞噬功能受损，并证实了P2X7抑制在体外和体内都恢复了小胶质细胞的吞噬功能。
Subarachnoid haemorrhage (SAH) has a high rate of disability and mortality. Extremely damaging molecules, including adenosine triphosphate (ATP), are released from extravasated red blood cells and nerve cells, which activate microglia and induce sterile tissue injury and organ dysfunction. P2X purinoceptor 7 (P2X7) is one of the most important purine receptors on the microglial surface and is involved in the proinflammatory activation of microglia. While P2X7 can also affect microglial phagocytosis, the mechanism is not clear. Here, we demonstrated that microglial phagocytosis is progressively impaired under continued BzATP exposure and P2X7 activation. Furthermore, we found that P2X7 activation leads to increased intracellular Ca2+ levels and activates Calcineurin, which dephosphorylates dynamin‐related protein 1 (DRP1) S637. The dephosphorylation of DRP1 at S637 leads to increased mitochondrial fission and decreased mitochondrial function, which may be responsible for the decreased microglial phagocytosis. Finally, we pharmacologically inhibited P2X7 activation in mice, which resulted in rescue of mitochondrial function and decreased microglial proliferation, but improved phagocytosis after SAH. Our study confirmed that P2X7 activation after SAH leads to the impairment of microglial phagocytosis through mitochondrial fission and verified that P2X7 inhibition restores microglial phagocytosis both in vitro and in vivo.
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影响因子：
4.6
作者：
Katoh M;Wu B;Nguyen HB;Thai TQ;Yamasaki R;Lu H;Rietsch AM;Zorlu MM;Shinozaki Y;Saitoh Y;Saitoh S;Sakoh T;Ikenaka K;Koizumi S;Ransohoff RM;Ohno N
通讯作者：
Ohno N
DOI：
10.1038/s41582-020-00447-8
发表时间：
2021-04
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Ballabh P;de Vries LS
通讯作者：
de Vries LS
影响因子：
7.3
作者：
Bhattacharya, Anindya;Wang, Qi;Letavic, Michael A.
通讯作者：
Letavic, Michael A.
影响因子：
--
作者：
Crowley, Lisa C;Christensen, Melinda E;Waterhouse, Nigel J
通讯作者：
Waterhouse, Nigel J
影响因子：
16.6
作者：
Jose Martinez-Garcia, Juan;Martinez-Banaclocha, Helios;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo