Department of Pain, Henan Province Hospital of TCM, The Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, China.
Department of Neurosurgery, The General Hospital of Northern Theater Command, Shenyang, 110840, China.
Exp Cell Res. 2021 Feb 1;399(1):112435. doi: 10.1016/j.yexcr.2020.112435. Epub 2020 Dec 16.
LncRNA embryonic stem cells expressed 1 (Lncenc1), named after its high expression in naïve embryonic stem cells (nESCs), has been rarely studied in almost all pathological processes. Evidences suggest that Lncenc1 is likely to work in the form of RNA-protein complex. Here, we found that Lncenc1 in dorsal root ganglion (DRG) was significantly upregulated in response to mouse nerve injury caused by partial sciatic nerve ligation (pSNL). Overexpression of Lncenc1 mediated by adenoviral expression vector promoted the activation of microglia and the production of inflammatory cytokines including TNF-α, IL-1β and MCP-1. In contrast, knockdown of Lncenc1 suppressed activation of microglia and production of inflammatory cytokines. In the mechanism exploration, we found that Lncenc1 could bind with the RNA binding protein (RBP) enhancer of zeste homologue 2 (EZH2), an identified contributor in microglial activation and neuropathic pain. Lncenc1 interacted with EZH2 and downregulated the expression of brain-specific angiogenesis inhibitor 1 (BAI1). Either inhibition of EZH2 or overexpression of BAI1 could reverse the effects of Lncenc1 overexpression on microglial activation and neuroinflammation. Finally, the Lncenc1-siRNA was intrathecally injected into pSNL mice, and its effects on neuropathic pain were evaluated. Knockdown of Lncenc1 attenuated the development and maintenance of mechanical and thermal hyperalgesia of pSNL mice, accompanied by an increase in BAI1 expression and decrease in inflammatory cytokines. In conclusion, Lncenc1 contributes to neuropathic pain by interacting with EZH2 and downregulating the BAI1 gene in mouse microglia.
长链非编码 RNA 胚胎干细胞表达 1（Lncenc1），因其在原始胚胎干细胞（nESCs）中的高表达而得名，在几乎所有病理过程中都很少被研究。有证据表明，Lncenc1 可能以 RNA-蛋白质复合物的形式发挥作用。在这里，我们发现，在小鼠坐骨神经部分结扎（pSNL）引起的神经损伤后，背根神经节（DRG）中的 Lncenc1 显著上调。通过腺病毒表达载体过表达 Lncenc1 可促进小胶质细胞的激活和促炎细胞因子的产生，包括 TNF-α、IL-1β 和 MCP-1。相反，敲低 Lncenc1 抑制小胶质细胞的激活和促炎细胞因子的产生。在机制探索中，我们发现 Lncenc1 可以与 RNA 结合蛋白（RBP）增强子 Zeste 同源物 2（EZH2）结合，EZH2 是小胶质细胞激活和神经病理性疼痛的一个确定的贡献者。Lncenc1 与 EZH2 相互作用，并下调脑特异性血管生成抑制剂 1（BAI1）的表达。EZH2 抑制或 BAI1 过表达均可逆转 Lncenc1 过表达对小胶质细胞激活和神经炎症的作用。最后，将 Lncenc1-siRNA 鞘内注射到 pSNL 小鼠中，评估其对神经病理性疼痛的影响。敲低 Lncenc1 可减轻 pSNL 小鼠机械性和热痛觉过敏的发展和维持，同时 BAI1 表达增加，促炎细胞因子减少。总之，Lncenc1 通过与 EZH2 相互作用并下调小鼠小胶质细胞中的 BAI1 基因，促进神经病理性疼痛的发生。
