A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.
A nerve injury-specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression.
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神经损伤特异性长非编码RNA通过增加Ccl2表达促进神经病理性疼痛
DOI：
10.1172/jci153563
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发表时间：
2022-07-01
期刊：
影响因子：
--
通讯作者：
Tao YX
中科院分区：
文献类型：
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作者：
Du S;Wu S;Feng X;Wang B;Xia S;Liang L;Zhang L;Govindarajalu G;Bunk A;Kadakia F;Mao Q;Guo X;Zhao H;Berkman T;Liu T;Li H;Stillman J;Bekker A;Davidson S;Tao YX
背根神经节（dorsal root ganglia，DRGs）神经损伤相关基因的不适应性改变是神经病理性疼痛发生的关键。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，我们确定了一个保守的lncRNA，命名为神经损伤特异性lncRNA（NIS-lncRNA），其上调损伤的DRG专门响应神经损伤。这种上调是由神经损伤诱导的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。在神经病理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CCL 2在受损DRG中的增加和伤害性超敏反应。模拟NIS-lncRNA上调升高了CCL2表达，增加了DRG神经元中CCL2介导的兴奋性，并产生了神经性疼痛症状。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表达而参与神经病理性疼痛，并且可能是神经病理性疼痛管理的潜在靶标。
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.