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 7

Upregulated NIS lncRNA is required for the SNL-induced CCL2 increase in injured DRGs of male mice.

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Upregulated NIS lncRNA is required for the SNL-induced CCL2 increase in ...
Data: mean ± SEM. (A) Level of Ccl2 mRNA in the cultured DRG neurons 3 days after transduction with AAV5-Gfp, AAV5-NIS V1, or AAV5-NIS V2. n = 5 repeats per group. *P < 0.05, **P < 0.01, by 2-tailed, unpaired Student’s t test. (B and C) Levels of Ccl2 mRNA and CCL2 protein in the ipsilateral L4 DRG after surgery. n = 20 mice per day per group. **P < 0.01, by 2-way (B) or 1-way (C) ANOVA with post hoc Tukey’s test. (D and E) Levels of NIS V1, NIS V2, and Ccl2 mRNA and CCL2 protein in the ipsilateral L4 DRG 14 days after surgery in the NIS-lncRNAfl/fl mice with microinjection of AAV5-Gfp or AAV5-Cre 35 days before surgery. n = 20 mice per group. **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test. (F and G) Levels of NIS V1, Ccl2 mRNA, and CCL2 protein in the ipsilateral L3/4 DRGs 5 days after DRG microinjection of Ccl2 siRNA (Ccl2-si) or scrambled siRNA (Scr-si) in mice with microinjection of AAV5-Gfp (Gfp) or AAV5-NIS V1 (V1) 35 days before siRNA microinjection. n = 10 mice per group. *P < 0.05, **P < 0.01, by 1-way ANOVA with post hoc Tukey’s test. (H and I) Levels of Ccl2 mRNA and CCL2 protein in the ipsilateral L3/4 DRGs 7 days after DRG microinjection of NIS lncRNA siRNA (NIS-si) or scrambled siRNA (Scr-si) in mice with microinjection of AAV5-Gfp or AAV5-Elf1 (Elf1) 35 days before siRNA microinjection. n = 10 mice per group. **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test.