TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model
TMEM16F Aggravates Neuronal Loss by Mediating Microglial Phagocytosis of Neurons in a Rat Experimental Cerebral Ischemia and Reperfusion Model
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TMEM16F 通过介导大鼠实验性脑缺血和再灌注模型中神经元的小胶质细胞吞噬作用加剧神经元损失
DOI：
10.3389/fimmu.2020.01144
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发表时间：
2020-07
影响因子：
7.3
通讯作者：
Gang Chen
中科院分区：
文献类型：
--
作者：
Yijie Zhang;Haiying Li;Xiang Li;Jie Wu;Tao Xue;Jiang Wu;Haitao Shen;Xiang Li;Meifen Shen;Gang Chen
脑缺血是一种严重的急性疾病，通常由脑血管疾病引起，导致高致残率和死亡率。吞噬作用是一种新认识的细胞死亡形式，由活细胞吞噬引起，据报道，它有助于缺血性卒中后脑组织中的神经元丢失。先前的数据表明，磷脂酰丝氨酸暴露于活的神经元可以诱导这些神经元的小胶质细胞吞噬。磷脂酰丝氨酸可以通过一种被称为TMEM16F的钙活化磷脂重组酶可逆地暴露于活细胞中。血小板膜上tmem16f介导的磷脂混乱对止血和血栓形成至关重要，在Scott综合征中起着重要作用，已被大量研究证实。然而，很少有研究探讨TMEM16F与缺血性脑卒中吞噬的关系。本研究采用成年雄性Sprague-Dawley大鼠体内脑中动脉闭塞/再灌注（MCAO/R）模型，体外对培养神经元进行氧-葡萄糖剥夺/再氧化（OGD/R）模拟脑缺血-再灌注（I/R）损伤。我们发现，体内和体外I/R损伤后12 h， TMEM16F蛋白水平均显著升高，并且在体外I/R损伤神经元中证实了可逆性磷脂酰丝氨酸暴露。此外，我们构建了LV-TMEM16F-RNAi转染系统，以抑制脑缺血期间和脑缺血后TMEM16F的表达。结果表明，TMEM16F敲低可通过抑制“吃我”信号磷脂酰丝氨酸，减轻运动功能损伤，减少半暗带活神经元的小胶质吞噬。我们的数据表明，通过缺乏TMEM16F来减少神经元磷脂酰丝氨酸暴露，可以阻断神经元的吞噬，并挽救半暗带中应激但仍有活力的神经元，这可能有助于减少梗死体积和改善功能恢复。
Cerebral ischemia is a severe, acute condition, normally caused by cerebrovascular disease, and results in high rates of disability, and death. Phagoptosis is a newly recognized form of cell death caused by phagocytosis of viable cells, and has been reported to contribute to neuronal loss in brain tissue after ischemic stroke. Previous data indicated that exposure of phosphatidylserine to viable neurons could induce microglial phagocytosis of such neurons. Phosphatidylserine can be reversibly exposed to viable cells as a result of a calcium-activated phospholipid scramblase named TMEM16F. TMEM16F-mediated phospholipid scrambling on platelet membranes is critical for hemostasis and thrombosis, which plays an important role in Scott syndrome and has been confirmed by much research. However, few studies have investigated the association between TMEM16F and phagocytosis in ischemic stroke. In this study, a middle-cerebral-artery occlusion/reperfusion (MCAO/R) model was used in adult male Sprague-Dawley rats in vivo, and cultured neurons were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate cerebral ischemia-reperfusion (I/R) injury in vitro. We found that the protein level of TMEM16F was significantly increased at 12 h after I-R injury both in vivo and in vitro, and reversible phosphatidylserine exposure was confirmed in neurons undergoing I/R injury in vitro. Additionally, we constructed a LV-TMEM16F-RNAi transfection system to suppress the expression of TMEM16F during and after cerebral ischemia. As a result, TMEM16F knockdown alleviated motor function injury and decreased the microglial phagocytosis of viable neurons in the penumbra through inhibiting the “eat-me” signal phosphatidylserine. Our data indicate that reducing neuronal phosphatidylserine-exposure via deficiency of TMEM16F blocks phagocytosis of neurons and rescues stressed-but-still-viable neurons in the penumbra, which may contribute to reducing infarct volume and improving functional recovering.
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影响因子：
4
作者：
Back, T
通讯作者：
Back, T
影响因子：
8.3
作者：
D. Saur;R. Buchert;R. Knab;C. Weiller;J. Röther
通讯作者：
D. Saur;R. Buchert;R. Knab;C. Weiller;J. Röther
DOI：
10.1177/0271678x18762637
发表时间：
2019-08
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Wang Z;Chen Z;Yang J;Yang Z;Yin J;Duan X;Shen H;Li H;Wang Z;Chen G
通讯作者：
Chen G
影响因子：
6.9
作者：
Trout AL;Kahle MP;Roberts JM;Marcelo A;de Hoog L;Boychuk JA;Grupke SL;Berretta A;Gowing EK;Boychuk CR;Gorman AA;Edwards DN;Rutkai I;Biose IJ;Ishibashi-Ueda H;Ihara M;Smith BN;Clarkson AN;Bix GJ
通讯作者：
Bix GJ
影响因子：
8.3
作者：
Ma S;Wang J;Wang Y;Dai X;Xu F;Gao X;Johnson J;Xu N;Leak RK;Hu X;Luo Y;Chen J
通讯作者：
Chen J