Epigenetic Modification of Spinal miR-219 Expression Regulates Chronic Inflammation Pain by Targeting CaMKIIγ
Epigenetic Modification of Spinal miR-219 Expression Regulates Chronic Inflammation Pain by Targeting CaMKIIγ
复制标题
脊髓 miR-219 表达的表观遗传修饰通过靶向 CaMKII gamma 调节慢性炎症疼痛
DOI：
10.1523/jneurosci.5346-13.2014
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发表时间：
2014-07-16
影响因子：
5.3
通讯作者：
Cao, Jun-Li
中科院分区：
文献类型：
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作者：
Pan, Zhiqiang;Zhu, Li-Jiao;Cao, Jun-Li
新兴证据表明，miRNA介导的基因表达调节导致慢性疼痛，但其功能调节机制仍然未知。在这里，我们发现完整的Freund辅助（CFA）诱导的慢性炎症疼痛显着降低了小鼠脊柱神经元中的miRNA-219（miR-219）表达。此外，在CFA小鼠中增加了脊柱CAMKII伽玛的表达，这是一个经过实验验证的miR-219靶标。脊柱miR-219的过表达阻止并逆转热痛觉过敏和机械性异常性和脊柱神经元敏感性，由CFA诱导。同时，miR-219的过表达逆转了脊柱CAMKIIγ的表达增加。天真小鼠中脊柱miR-219的下调引起疼痛响应行为和p-nMDAR1表达增加，这可以通过camkii伽玛的敲低来抑制。甲硫酸氢盐测序表明，CFA诱导miR-219启动子中CpG岛的高甲基化。用脱甲基化剂5'-aza-2'-脱氧胞苷的治疗显着减弱疼痛行为和脊髓神经元敏化，并伴随着脊髓miR-219的增加和CAMKIIγ表达的降低。我们一起得出结论，甲基化介导的脊柱miR-219表达的表观遗传学修饰通过靶向CAMKII伽玛来调节慢性炎症性疼痛。
Emerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly reduced miRNA-219 (miR-219) expression in mice spinal neurons. Furthermore, the expression of spinal CaMKII gamma, an experimentally validated target of miR-219, was increased in CFA mice. Overexpression of spinal miR-219 prevented and reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization induced by CFA. Concurrently, increased expression of spinal CaMKII gamma was reversed by miR-219 overexpression. Downregulation of spinal miR-219 in naive mice induced pain-responsive behaviors and increased p-NMDAR1 expression, which could be inhibited by knockdown of CaMKII gamma. Bisulfite sequencing showed that CFA induced the hypermethylation of CpG islands in the miR-219 promoter. Treatment with demethylation agent 5'-aza-2'-deoxycytidine markedly attenuated pain behavior and spinal neuronal sensitization, which was accompanied with the increase of spinal miR-219 and decrease of CaMKII gamma expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKII gamma.