Epigenetic reduction of miR-214-3p upregulates astrocytic colony-stimulating factor-1 and contributes to neuropathic pain induced by nerve injury
Epigenetic reduction of miR-214-3p upregulates astrocytic colony-stimulating factor-1 and contributes to neuropathic pain induced by nerve injury
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DOI：
10.1097/j.pain.0000000000001681
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发表时间：
2020-01-01
期刊：
影响因子：
7.4
通讯作者：
Tang, Yuying
中科院分区：
文献类型：
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作者：
Liu, Lian;Xu, Dan;Tang, Yuying
新的证据表明，集落刺激因子-1(CSF1)调节中枢神经系统的神经炎症和神经病理性疼痛的发生，但其潜在的机制尚不清楚。在这里，我们证实了脊神经结扎(SNL)大鼠同侧背角中活化的星形胶质细胞来源的CSF1表达增加。抑制CSF1的表达可以减轻神经炎症、神经元的超兴奋性和背角谷氨酸受体亚单位的上调，并改善SNL诱导的疼痛行为。我们还发现SNL术后同侧背角miR-214-3p的表达减少，miR-214-3p直接与CSF1 mRNA的3‘-UTR区结合，负调控CSF1的表达。鞘内注射miR-214-3p可逆转CSF1的表达增强和星形胶质细胞的过度活动，减轻SNL诱导的IL-6上调和疼痛行为。此外，抑制脊髓miR-214-3p可增强星形胶质细胞的反应性，促进CSF1和IL-6的产生，并诱导幼年动物的疼痛过敏。此外，SNL还诱导了与miR-214-3p启动子高甲基化相关的DNA甲基转移酶3a(DNMT3a)的表达，导致模型鼠miR-214-3p的表达降低。用DNMT抑制剂ZeBularine治疗显著减少SNL大鼠同侧背角miR-214-3p基因启动子胞嘧啶的甲基化，从而增加miR-214-3p的表达，减少CSF1的含量，进而抑制IL-6的产生和疼痛行为。综上所述，我们的数据表明，DNMT3a介导的miR-214-3p的表观遗传抑制促进了星形胶质细胞CSF1的产生，从而导致SNL模型大鼠的神经炎症和疼痛行为。
Emerging evidence has indicated that colony-stimulating factor-1 (CSF1) modulates neuroinflammation in the central nervous system and the development of neuropathic pain, while the underlying mechanism remains unknown. Here, we identified the increased expression of CSF1 derived from activated astrocytes in the ipsilateral dorsal horn in rats with spinal nerve ligation (SNL). Suppression of CSF1 expression alleviated neuroinflammation, neuronal hyperexcitability, and glutamatergic receptor subunit upregulation in the dorsal horn and improved SNL-induced pain behavior. We also found reduced miR-214-3p expression in the ipsilateral dorsal horn following an SNL procedure; miR-214-3p directly bound to the 3 '-UTR of CSF1 mRNA and negatively regulated CSF1 expression. Intrathecal delivery of miR-214-3p mimic reversed the enhanced expression of CSF1 and astrocyte overactivity and alleviated the IL-6 upregulation and pain behavior induced by SNL. Moreover, suppression of spinal miR-214-3p increased astrocyte reactivity, promoted CSF1 and IL-6 production, and induced pain hypersensitivity in naive animals. Furthermore, SNL induced the expression of DNA methyltransferase 3a (DNMT3a) that was associated with the hypermethylation of the miR-214-3p promoter, leading to reduced miR-214-3p expression in the model rodents. Treatment with the DNMT inhibitor zebularine significantly reduced cytosine methylation in the miR-214-3p promoter; this reduced methylation consequently increased the expression of miR-214-3p and decreased the content of CSF1 in the ipsilateral dorsal horn and, further, attenuated IL-6 production and pain behavior in rats with SNL. Together, our data indicate that the DNMT3a-mediated epigenetic suppression of miR-214-3p enhanced CSF1 production in astrocytes, which subsequently induced neuroinflammation and pain behavior in SNL model rats.