TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways.
TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-κB pathways.
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TRAF3 通过靶向 TAK1 依赖性 MAPK 和 NF-κ B 通路介导蛛网膜下腔出血后早期脑损伤中的神经元凋亡
DOI：
10.1038/s41419-020-03278-z
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发表时间：
2021-01-07
影响因子：
9
通讯作者：
Hang C
中科院分区：
文献类型：
--
作者：
Zhou Y;Tao T;Liu G;Gao X;Gao Y;Zhuang Z;Lu Y;Wang H;Li W;Wu L;Zhang D;Hang C
神经元凋亡在蛛网膜下腔出血（SAH）后早期脑损伤（EBI）中起重要作用。TRAF 3被报道为脑卒中管理的有希望的治疗靶点，其涵盖了几个神经元凋亡信号级联。因此，本研究旨在确定TRAF 3的下调是否可以在SAH诱导的EBI中起到神经保护作用。通过血管内穿孔建立小鼠体内SAH模型。同时，采用原代培养的小鼠皮层神经元经氧血红蛋白处理后，体外模拟SAH。我们的研究结果表明，TRAF 3蛋白表达增加，并在体内和体外SAH模型的神经元中表达。TRAF 3 siRNA逆转了SAH小鼠的神经元丢失并改善了神经功能缺损，并减少了SAH原代神经元的细胞死亡。从机制上讲，我们发现TRAF 3直接与TAK 1结合，并增强TAK 1的磷酸化和活化，从而进一步增强NF-κB和MAPK途径的活化，诱导神经元凋亡。重要的是，TRAF 3表达在SAH后人脑组织中升高，主要在神经元中表达。总之，我们的研究表明，TRAF 3是通过与TAK 1相互作用和激活SAH诱导的EBI中MAPK和NF-κB通路的上游调节因子。此外，TRAF 3可能作为一个新的治疗靶点在SAH诱导的EBI。
Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.
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影响因子：
30.5
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影响因子：
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Fujii, Mutsumi;Yan, Junhao;Rolland, William B.;Soejima, Yoshiteru;Caner, Basak;Zhang, John H.
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Zhang, John H.
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影响因子：
9
作者：
Luo C;Yao X;Li J;He B;Liu Q;Ren H;Liang F;Li M;Lin H;Peng J;Yuan TF;Pei Z;Su H
通讯作者：
Su H
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1.5
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Sabri M;Lass E;Macdonald RL
通讯作者：
Macdonald RL