A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression
Shibin Du, … , Steve Davidson, Yuan-Xiang Tao
Shibin Du, … , Steve Davidson, Yuan-Xiang Tao
Published July 1, 2022
Citation Information: J Clin Invest. 2022;132(13):e153563. https://doi.org/10.1172/JCI153563.
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Research Article Cell biology Neuroscience

A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression

Abstract

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.

Authors

Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao

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Figure 9

DRG overexpression of NIS-lncRNA increases CCL2-mediated DRG neuronal excitability.

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DRG overexpression of NIS-lncRNA increases CCL2-mediated DRG neuronal ex...
Data: mean ± SEM. (A and B) Levels of NIS V1 and CCL2 protein in the ipsilateral L3/4 DRGs 4 weeks after microinjection of AAV5-Gfp alone (Gfp) or a mixture of AAV5-Gfp and AAV5-V1 (NIS) into unilateral L3/4 DRGs of WT or Ccl2-KO mice. n = 10 mice per group. **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test. (C and D) Resting membrane potentials (RMP) and rheobases. n = 22 small, 23 medium, and 20 large cells from 14 Gfp-microinjected WT mice; n = 24 small, 24 medium, and 22 large cells from 18 NIS-microinjected WT mice; n = 24 small, 24 medium, and 22 large cells from 18 NIS-microinjected Ccl2-KO mice. *P < 0.05, **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test. (E–H) Numbers of evoked action potentials after application of different currents as indicated. (E) Representative traces of evoked action potentials (100 pA, 500 ms) in small DRG neurons. Numbers of recorded cells and mice used are the same as in C and D. *P < 0.05 vs. Gfp-microinjected WT mice at the corresponding injected intensity and #P < 0.05 vs. NIS-microinjected WT mice at the corresponding injected intensity, by 2-way ANOVA with post hoc Tukey’s test. (I and J) Frequencies of spontaneous activity (SA). (I) Representative SA traces of small DRG neurons. Numbers of recorded cells and mice used are the same as in C and D. *P < 0.05, **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test.