Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK-STAT Pathway.
Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK-STAT Pathway.
复制标题
DOI：
10.1007/s12035-017-0432-7
复制
发表时间：
2018-03
影响因子：
5.1
通讯作者：
Shah ZA
中科院分区：
文献类型：
--
作者：
Alhadidi Q;Shah ZA
小胶质细胞在中枢神经系统中对不同类型的损伤或应激反应而被激活。这种激活对于清除有害物质和恢复组织稳态是必要的。然而，小胶质细胞的过度激活是有害的，并有助于继发性损伤。相关地，在许多临床前和临床研究中靶向小胶质细胞活性，但这种策略在临床试验中失败。失败的主要原因是损伤机制的复杂性，需要联合治疗或靶向参与多个途径的过程。Cofilin是一种参与肌动蛋白动力学的细胞骨架相关蛋白。在我们以前的研究中，我们证明了在OGD条件下cofilin介导神经元凋亡的作用。先前对小胶质细胞的研究表明，cofilin参与ROS的形成和吞噬作用。然而，需要更多的研究来描述cofilin在小胶质细胞活化中的作用。因此，在目前的研究中，我们研究了cofilin在LPS诱导的小胶质细胞活化中的作用，使用cofilin siRNA敲低范例。分化的PC 12细胞的存活力被用作来自cofilin siRNA转染和LPS活化的小胶质细胞的条件培养基的神经毒性潜力的量度。Cofilin基因敲低可显著抑制LPS通过NF-κB和JAK-STAT途径诱导的小胶质细胞活化。cofilin基因敲低可显著降低促炎介质（NO、TNF-α、iNOS和COX 2）的释放以及小胶质细胞的增殖和迁移率。此外，分化的PC 12细胞被保护免受来自cofilin转染和LPS激活的小胶质细胞的条件培养基诱导的神经毒性。总之，我们证明了cofilin参与了小胶质细胞激活的级联反应，并进一步验证了我们先前关于cofilin介导神经元凋亡的研究。总之，我们的研究结果表明，cofilin可以在神经元和小胶质细胞中呈现共同的靶点，并且可能被证明是包括中风在内的不同脑损伤机制的有希望的疗法。
Microglial cells are activated in response to different types of injuries or stress in the CNS. Such activation is necessary to get rid of the injurious agents and restore tissue homeostasis. However, excessive activation of microglial cells is harmful and contributes to secondary injury. Pertinently, microglial cell activity was targeted in many preclinical and clinical studies but such strategy failed in clinical trials. The main reason behind the failed attempts is the complexity of the injury mechanisms which needs either a combination therapy or targeting a process that is involved in multiple pathways. Cofilin is a cytoskeleton associated protein involved in actin dynamics. In our previous study, we demonstrated the role of cofilin in mediating neuronal apoptosis during OGD conditions. Previous studies on microglia have shown the involvement of cofilin in ROS formation and phagocytosis. However, additional studies are needed to delineate the role of cofilin in microglial cell activation. Therefore, in the current study, we investigated the role of cofilin in LPS-induced microglial cell activation using cofilin siRNA knockdown paradigms. The viability of differentiated PC12 cells was used as a measure of the neurotoxic potential of conditioned medium derived from cofilin siRNA-transfected and LPS-activated microglial cells. Cofilin knockdown significantly inhibited LPS-induced microglial cell activation through NF-κB and JAK-STAT pathways. The release of proinflammatory mediators (NO, TNF-α, iNOS and COX2) as well as microglial proliferation and migration rates were significantly reduced by cofilin knockdown. Furthermore, differentiated PC12 cells were protected from the neurotoxicity induced by conditioned medium derived from cofilin-transfected and LPS-activated microglial cells. In conclusion, we demonstrated that cofilin is involved in the cascade of microglial cell activation and further validates our previous study on cofilin’s role in mediating neuronal apoptosis. Together, our results suggest that cofilin could present a common target in neurons and microglial cells and might prove to be a promising therapy for different brain injury mechanisms including stroke.
登录
查看更多内容
影响因子：
5.5
作者：
Kim JY;Kim N;Yenari MA
通讯作者：
Yenari MA
影响因子：
9.3
作者：
Hadas S;Spira M;Hanisch UK;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
5.3
作者：
Gitik M;Kleinhaus R;Hadas S;Reichert F;Rotshenker S
通讯作者：
Rotshenker S
影响因子：
9.3
作者：
Gouix, Elsa;Buisson, Alain;Had-Aissouni, Laurence
通讯作者：
Had-Aissouni, Laurence
影响因子：
4.8
作者：
Fazal, Fabeha;Bijli, Kaiser M.;Rahman, Arshad
通讯作者：
Rahman, Arshad