EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain.
EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain.
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我们和其他人最近的研究表明，增强子zeste同源物-2（EZH 2），一种组蛋白甲基转移酶，在神经胶质细胞中通过调节促炎细胞因子和趋化因子的产生来调节神经病理性疼痛的发生。本文综述了近年来该领域的研究进展。EZH 2是多梳抑制复合物2（PRC 2）的亚基，其主要作为组蛋白甲基转移酶催化组蛋白3在赖氨酸27（H3 K27）上的甲基化，最终导致转录抑制。患有神经性疼痛的动物表现出受损神经、脊髓和前扣带皮层的EZH 2活性和神经炎症增加。用DZNep或GSK-126抑制EZH 2改善神经炎症和神经性疼痛。Toll样受体4和降钙素基因相关肽受体激活、miR-124- 3 p和miR-378 microRNA下调或Lncenc 1和MALAT 1长非编码RNA上调后，EZH 2蛋白表达增加。EZH 2抑制的基因包括细胞因子信号传导抑制因子3（SOCS 3）、核因子（红细胞衍生2）样2因子（NrF 2）、miR-29 b-3 p、miR-146 a-5 p和脑特异性血管生成抑制因子1（BAI 1）。促炎介质通过使外周中的伤害感受器敏感以及增强CNS中的兴奋性突触活动和抑制抑制性突触活动来促进沿着沿着疼痛信号传导途径的神经元活化。这些研究共同揭示了EZH 2与已知是神经炎症过程和神经性疼痛发生的关键参与者的信号通路有关。因此，靶向EZH 2信号通路可能为减轻神经炎症和神经性疼痛开辟新的途径。
Recent studies by us and others have shown that enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, in glial cells regulates the genesis of neuropathic pain by modulating the production of proinflammatory cytokines and chemokines. In this review, we summarize recent advances in this research area. EZH2 is a subunit of polycomb repressive complex 2 (PRC2), which primarily serves as a histone methyltransferase to catalyze methylation of histone 3 on lysine 27 (H3K27), ultimately resulting in transcriptional repression. Animals with neuropathic pain exhibit increased EZH2 activity and neuroinflammation of the injured nerve, spinal cord, and anterior cingulate cortex. Inhibition of EZH2 with DZNep or GSK-126 ameliorates neuroinflammation and neuropathic pain. EZH2 protein expression increases upon activation of Toll-like receptor 4 and calcitonin gene-related peptide receptors, downregulation of miR-124-3p and miR-378 microRNAs, or upregulation of Lncenc1 and MALAT1 long noncoding RNAs. Genes suppressed by EZH2 include suppressor of cytokine signaling 3 (SOCS3), nuclear factor (erythroid-derived 2)-like-2 factor (NrF2), miR-29b-3p, miR-146a-5p, and brain-specific angiogenesis inhibitor 1 (BAI1). Pro-inflammatory mediators facilitate neuronal activation along pain-signaling pathways by sensitizing nociceptors in the periphery, as well as enhancing excitatory synaptic activities and suppressing inhibitory synaptic activities in the CNS. These studies collectively reveal that EZH2 is implicated in signaling pathways known to be key players in the process of neuroinflammation and genesis of neuropathic pain. Therefore, targeting the EZH2 signaling pathway may open a new avenue to mitigate neuroinflammation and neuropathic pain.
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