Inhibition of lncRNA DILC attenuates neuropathic pain via the SOCS3/JAK2/STAT3 pathway
Inhibition of lncRNA DILC attenuates neuropathic pain via the SOCS3/JAK2/STAT3 pathway
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DOI：
10.1042/bsr20194486
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发表时间：
2020-06-17
影响因子：
4
通讯作者：
Xue, Jing
中科院分区：
文献类型：
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作者：
Liu, Yujie;Feng, Lu;Xue, Jing
长非编码RNA(LncRNAs)参与了包括神经病理性疼痛在内的多种病理过程。本研究旨在探讨肝癌干细胞(DILC)下调表达的LncRNA在神经病理性疼痛发生发展中的作用及其机制。采用双侧慢性压迫损伤(BCCI)方法建立神经病理性疼痛大鼠模型。脊髓定量聚合酶链式反应分析结果显示，与假手术组相比，BCCI组大鼠脊髓DILC表达明显上调。鞘内注射DILC siRNA介导的DILC下调可显著提高BCCI大鼠的机械收缩阈值(MWT)和缩足阈值潜伏期(PWTL)，降低神经冷敏感性阳性率，抑制炎症基因的表达。下调DILC可诱导脊髓组织细胞因子信号转导抑制因子3(SOCS3)的表达，抑制信号转导和转录激活因子3(p-STAT3)的磷酸化。Western blotting结果显示，DILC siRNA表达下调可诱导原代小胶质细胞SOCS3表达，并抑制p-Janus kinase2(p-JAK2)和p-STAT3及其下游基因的表达。此外，DILC的下调增加了原代小胶质细胞的活力，抑制了细胞凋亡，并抑制了小胶质细胞产生IL-6和IL-1β。相反，DILC的过表达与DILC基因敲除的功能相反。总之，沉默的lncRNA DILC通过抑制SOCS3诱导的JAK2/STAT3通路减轻神经病理性疼痛。
Long noncoding RNAs (lncRNAs) have been involved in the development of multiple pathological processes including neuropathic pain. The aim of the present study is to investigate the role of lncRNA down-regulated in liver cancer stem cells (DILC) in the progression of neuropathic pain and its underlying mechanism. Neuropathic pain rat model was established with the bilateral chronic constriction injury (bCCI) method. The results from quantitative PCR analysis in the spinal cord showed that DILC was significantly up-regulated in rats with bCCI compared with the sham group. DILC down-regulation mediated by intrathecal administration of DILC siRNA significantly increased the mechanical shrinkage threshold (MWT) and paw withdrawal threshold latency (PWTL), decreased the positive frequency for nerve sensitivity to cold and suppressed the expression of inflammatory genes in bCCI rats. Down-regulation of DILC induced suppressor of cytokine signaling (SOCS3) expression and inhibited the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in spinal cord tissues. Western blotting showed that down-regulation of DILC by DILC siRNA transfection induced SOCS3 expression and inhibited the expression of p-Janus kinase 2 (p-JAK2) and p-STAT3 and their downstream genes in primary microglia. Furthermore, down-regulation of DILC increased the viability of primary microglia, suppressed apoptosis, and inhibited the production of interleukin (IL)-6 and IL-1 beta in microglia. In contrast, overexpression of DILC showed the opposite functions to those of DILC knockdown. In conclusion, silence of lncRNA DILC attenuates neuropathic pain via SOCS3-induced suppression of the JAK2/STAT3 pathway.