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MKP1 reduces neuroinflammation via inhibiting endoplasmic reticulum stress and mitochondrial dysfunction

机译:通过抑制MKP1减少神经炎症内质网压力和线粒体功能障碍

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MAP kinase phosphatase 1 (MKP1) has been identified as an antiapoptotic protein via sustaining mitochondrial function. However, the role of MKP1 in neuroinflammation has not been fully understood. The aim of this study is to figure out the influence of MKP1 in lipopolysaccharide (LPS)-treated microglia BV-2 cells and investigate whether MKP1 reduces BV-2 cell death via modulating endoplasmic reticulum (ER) stress and mitochondrial dysfunction. The results of this study demonstrated that MKP1 was rapidly downregulated after exposure to LPS. However, the transfection of MKP1 adenovirus could reverse cell viability and attenuate LPS-mediated BV-2 cell apoptosis. Mechanistically, MKP1 overexpression alleviated ER stress and corrected LPS-induced calcium overloading. Besides, MKP1 adenovirus transfection also reversed mitochondrial bioenergetics, maintained mitochondrial membrane potential, and blocked mitochondria-initiated apoptosis signals. Furthermore, we found that MKP1 overexpression is associated with inactivation of mitogen-activated protein kinase-c-Jun N-terminal kinase (MAPK-JNK) pathway. Interestingly, the activation of MAPK-JNK pathway could abolish the protective effects of MKP1 on BV-2 cells survival and mitochondrial function in the presence of LPS. Altogether, our results identified MKP1 as a primary defender of neuroinflammation via modulating ER stress and mitochondrial function in a manner dependent on MAPK-JNK pathway. These findings may open a new window for the treatment of neuroinflammation in the clinical setting.
机译:MAP激酶磷酸酶1 (MKP1)作为一个抗凋亡蛋白通过识别维持线粒体功能。没有MKP1的神经炎症的作用完全理解。找出MKP1的影响脂多糖(LPS)对小胶质细胞BV-2细胞和调查MKP1是否减少BV-2通过调节内质网细胞死亡(ER)压力和线粒体功能障碍。本研究的结果表明,MKP1暴露于LPS后迅速表达下调。然而,MKP1腺病毒转染可以逆转细胞生存能力和减弱LPS-mediated BV-2细胞凋亡。从力学上看,MKP1过度缓解ER压力和纠正LPS-induced钙重载。转染也逆转了线粒体生物能疗法,保持线粒体膜mitochondria-initiated潜力,阻塞细胞凋亡信号。MKP1过度有关失活的增殖作用kinase-c-Jun n端激酶(MAPK-JNK)途径。MAPK-JNK通路可能取消保护MKP1对BV-2细胞生存的影响线粒体功能的有限合伙人的存在。总之,我们的结果MKP1作为标识主要通过后卫的神经炎症调制ER应激和线粒体功能在某种程度上依赖MAPK-JNK通路。结果治疗可能会打开一个新窗口神经炎症的临床设置。

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