The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke.
The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke.
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坏死性凋亡的关键调节因子 RIP1 激酶有助于缺血性中风中星形胶质细胞增生和神经胶质疤痕的形成
DOI：
10.1007/s12975-021-00888-3
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发表时间：
2021-12
影响因子：
6.9
通讯作者：
Zhang HL
中科院分区：
文献类型：
--
作者：
Zhu YM;Lin L;Wei C;Guo Y;Qin Y;Li ZS;Kent TA;McCoy CE;Wang ZX;Ni Y;Zhou XY;Zhang HL
坏死性凋亡的启动依赖于受体相互作用蛋白1激酶（RIP 1 K）。我们最近报道，RIP 1 K的遗传和药理学抑制产生对缺血性卒中诱导的星形胶质细胞损伤的保护作用。然而，RIP 1 K在缺血性卒中诱导的星形胶质细胞增生和胶质瘢痕形成中的作用仍然未知。在这里，在短暂的大脑中动脉闭塞（tMCAO）大鼠模型和氧和葡萄糖剥夺和再给氧（OGD/Re）诱导的星形胶质细胞损伤模型，我们表明，RIP 1 K显着升高的反应性星形胶质细胞。敲低RIP 1 K或延迟给予RIP 1 K抑制剂Nec-1可下调胶质瘢痕标记物，改善缺血性卒中诱导的坏死形态和神经功能缺损，并减少脑萎缩体积。此外，敲低RIP 1 K减弱了星形胶质细胞的死亡和增殖，并促进神经元和星形胶质细胞共培养系统中神经元轴突的产生。血管内皮生长因子D（VEGF-D）及其受体VEGFR-3在反应性星形胶质细胞中均升高;同时，VEGF-D在暴露于OGD/Re的星形胶质细胞培养基中增加。RIP 1 K的敲低下调了反应性星形胶质细胞中VEGF-D基因和蛋白水平。用400 ng/ml重组VEGF-D处理诱导胶质瘢痕形成;相反，VEGFR-3抑制剂抑制OGD/Re诱导的胶质瘢痕形成。RIP 3 K和MLKL可能参与胶质瘢痕形成。总之，这些结果表明，RIP 1 K通过损害正常星形胶质细胞反应和增强星形胶质细胞VEGF-D/VEGFR-3信号通路参与星形胶质细胞增生和胶质瘢痕的形成。抑制RIP 1 K部分通过抑制星形胶质细胞增生和胶质瘢痕的形成促进脑功能恢复。
Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar.Graphical Abstract
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
影响因子：
6.2
作者：
Begum G;Song S;Wang S;Zhao H;Bhuiyan MIH;Li E;Nepomuceno R;Ye Q;Sun M;Calderon MJ;Stolz DB;St Croix C;Watkins SC;Chen Y;He P;Shull GE;Sun D
通讯作者：
Sun D
影响因子：
3.7
作者：
Cengiz P;Kintner DB;Chanana V;Yuan H;Akture E;Kendigelen P;Begum G;Fidan E;Uluc K;Ferrazzano P;Sun D
通讯作者：
Sun D
小胶质细胞坏死性凋亡通过 TLR4 激活导致神经炎症和视网膜变性
影响因子：
12.4
作者：
Huang Z;Zhou T;Sun X;Zheng Y;Cheng B;Li M;Liu X;He C
通讯作者：
He C
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV