Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway.
Fetuin-A alleviates neuroinflammation against traumatic brain injury-induced microglial necroptosis by regulating Nrf-2/HO-1 pathway.
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胎球蛋白-A通过调节Nrf-2/HO-1通路减轻创伤性脑损伤引起的小胶质细胞坏死性凋亡的神经炎症
DOI：
10.1186/s12974-022-02633-5
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发表时间：
2022-11-04
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
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作者：
小胶质细胞介导的炎症反应是创伤性脑损伤后继发性损伤的重要机制，但小胶质细胞激活的潜在机制尚不清楚。用成年雄性C57BL/6J小鼠诱导控制性皮质撞击(CCI)，用谷氨酸建立原代小胶质细胞损伤模型。免疫印迹和免疫染色检测小胶质细胞的活化。采用双抗体夹心酶联免疫吸附试验检测炎症因子。用免疫印迹和MitoSox红染色检测氧化应激标志物和线粒体活性氧(ROS)。用透射电子显微镜观察坏死性细胞的典型形态。我们的定量蛋白质组学鉴定出2499个蛋白质；在CCI后6h(CCI6h)组和Sham组之间，157个蛋白质在脑组织中有显著差异表达，在CCI24小时组和Sham组之间，109个蛋白质有显著差异表达。此外，与假手术组相比，CCI组的“急性期反应”、“炎症”和“蛋白质结合”等术语显著丰富。胎球蛋白-A是一种肝脏分泌的急性时相糖蛋白，参与了这些生物学过程。利用实验性脑损伤模型，我们发现胎球蛋白-A水平在6h达到峰值，然后逐渐下降。重要的是，我们发现，给予胎球蛋白-A可减少皮质损伤体积和水肿面积，并抑制炎症反应，这与抑制小胶质细胞坏死性下垂，从而减少小胶质细胞的激活有关。此外，给予胎球蛋白-A可减轻谷氨酸处理的小胶质细胞中线粒体的氧化应激，这是抑制坏死性下垂的关键机制。此外，我们还发现，胎球蛋白-A处理促进了核因子红系相关因子2(NRF-2)从胞浆到胞核的移位；然而，NRF-2抑制剂ML385和单血红素加氧酶-1(si-HO-1)阻断了胎球蛋白-A对氧化应激的调节，并诱导谷氨酸处理的小胶质细胞ROS水平增加和坏死。在体内和体外，胎球蛋白-A也可以保护神经元免受不利因素的影响。我们的结果表明，胎球蛋白-A激活了NRF-2/HO-1，抑制了氧化应激和坏死性下垂的水平，从而减轻了颅脑损伤后的异常炎症反应。这一发现为脑外伤的治疗提供了一种潜在的治疗策略。网上版载有补充材料，可在10.1186/s12974-022-02633-5查阅。
The microglia-mediated inflammatory response is a vital mechanism of secondary damage following traumatic brain injury (TBI), but the underlying mechanism of microglial activation is unclear. Controlled cortical impact (CCI) was induced in adult male C57BL/6J mice, and glutamate was used to construct a classical in vitro injury model in the primary microglia. Microglial activation was determined by western blot and immunostaining. The inflammatory factors were measured by enzyme-linked immunosorbent assay. The oxidative stress marker and mitochondrial reactive oxygen species (ROS) were measured by immunoblotting and MitoSox Red staining. Transmission electron microscopy was used to observe the typical morphology of necroptotic cells. Our quantitative proteomics identified 2499 proteins; 157 were significantly differentially expressed in brain tissue between the 6 h after CCI (CCI6h) group and sham group, and 109 were significantly differentially expressed between the CCI24h and sham groups. Moreover, compared with the sham group, the terms “acute-phase response”, “inflammation”, and “protein binding” were significantly enriched in CCI groups. Fetuin-A, a liver-secreted acute-phase glycoprotein, was involved in these biological processes. Using an experimental TBI model, we found that the Fetuin-A level peaked at 6 h and then decreased gradually. Importantly, we showed that administration of Fetuin-A reduced the cortical lesion volume and edema area and inhibited the inflammatory response, which was associated with suppressing microglial necroptosis, thus decreasing microglial activation. Furthermore, administration of Fetuin-A attenuated mitochondrial oxidative stress in glutamate-treated microglial cells, which is a critical mechanism of necroptosis suppression. In addition, we demonstrated that Fetuin-A treatment promoted translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus in vivo; however, the Nrf-2 inhibitor ML385 and si-heme oxygenase-1 (si-HO-1) disrupted the regulation of oxidative stress by Fetuin-A and induced increased ROS levels and necroptosis in glutamate-treated microglial cells. Fetuin-A also protected neurons from adverse factors in vivo and in vitro. Our results demonstrated that Fetuin-A activated Nrf-2/HO-1, suppressed oxidative stress and necroptosis levels, and thereby attenuates the abnormal inflammatory response following TBI. The findings suggest a potential therapeutic strategy for TBI treatment. The online version contains supplementary material available at 10.1186/s12974-022-02633-5.
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影响因子：
9.3
作者：
Chen X;Wu S;Chen C;Xie B;Fang Z;Hu W;Chen J;Fu H;He H
通讯作者：
He H
影响因子：
4.2
作者：
Ji, Jing;Tyurina, Yulia Y.;Bayir, Huelya
通讯作者：
Bayir, Huelya
影响因子：
9.3
作者：
Folkersma H;Foster Dingley JC;van Berckel BN;Rozemuller A;Boellaard R;Huisman MC;Lammertsma AA;Vandertop WP;Molthoff CF
通讯作者：
Molthoff CF
影响因子：
9.8
作者：
Gomez, Luis M.;Anton, Lauren;Parry, Samuel
通讯作者：
Parry, Samuel
影响因子：
6.1
作者：
Bischoff, Luc J. M.;Kuijper, Isoude A.;van de Water, Bob
通讯作者：
van de Water, Bob