Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

中文翻译：

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神经损伤特异性长链非编码 RNA 通过增加 Ccl2 表达促进神经性疼痛

背根神经节 (DRG) 中神经损伤相关基因的适应不良变化对于神经性疼痛的发生至关重要。新出现的证据支持长链非编码 RNA (lncRNA) 在调节基因转录中的作用。在这里，我们鉴定了一种保守的 lncRNA，命名为神经损伤特异性 lncRNA ( NIS-lncRNA )，因为它在受损的 DRG 中上调专门响应神经损伤。这种上调是由神经损伤引起的 DRG ELF1 增加触发的，DRG ELF1 是一种与NIS-lncRNA启动子结合的转录因子。在神经性疼痛的发展和维持期间，阻断这种上调减弱了神经损伤诱导的受损 DRG 中的 CCL2 增加和伤害性超敏反应。模拟NIS-lncRNA上调可提高 CCL2 表达，增加 CCL2 介导的 DRG 神经元兴奋性，并产生神经性疼痛症状。从机制上讲，NIS-lncRNA募集了更多的 RNA 相互作用蛋白 FUS 与Ccl2启动子的结合，并增强了受损 DRG 中的Ccl2转录。因此，NIS-lncRNA可能通过促进 FUS 触发的 DRG Ccl2表达参与神经性疼痛，并且可能是神经性疼痛管理的潜在靶点。