神经损伤引起的神经性疼痛是一种与神经炎症反应和神经元死亡相关的慢性疼痛;然而潜在的分子机制仍不清楚。双特异性磷酸酶8(DUSP8)可以介导许多细胞事件,但它是否与神经性疼痛有关尚不清楚。在研究中,我们发现脊神经结扎(SNL)手术对大鼠同侧脊髓(ISC)组织中DUSP8的表达水平明显降低。始终如一,脂多糖(LPS)暴露也降低了鼠类小胶质细胞中的DUSP8。发现腺相关病毒(AAV)介导的DUSP8过表达可显着改善SNL诱导的大鼠神经性疼痛。此外,SNL手术后,AAV-DUSP8也减轻了ISC组织中的神经元死亡。此外,通过抑制核因子κB(NF-κB)信号传导,在DUSP8过度表达时,SNL触发的神经炎症和小胶质细胞活化也得到缓解。在暴露于LPS的小胶质细胞中进行了验证。重要的是,我们的体外实验表明,小胶质细胞的炎症反应导致神经元死亡,DUSP8过表达也可以改善这种效应。值得注意的是,我们发现DUSP8与小胶质细胞中的转化生长因子β激活激酶-1(TAK1)直接相互作用。SNL和LPS均导致TAK1/p38/JNK1/2信号的激活,而被DUSP8强烈废除。有趣的是,TAK1阻断显著减少LPS诱导的炎症和神经元死亡,而被DUSP8击倒加速,进一步表明DUSP8改善的神经性疼痛在很大程度上依赖于TAK1.一起,我们的所有研究结果表明,DUSP8/TAK1信号传导可能是缓解神经性疼痛的潜在靶点.
Nerve injury-induced neuropathic pain is a type of chronic pain associated with neuroinflammatory response and neuronal death; however the underlying molecular mechanisms are still unclear. Dual-specificity phosphatase 8 (
DUSP8) can mediate numerous cellular events, but whether it\'s involved in neuropathic pain is unknown. In the study, we found that spinal nerve ligation (SNL) operation on rats significantly decreased
DUSP8 expression levels in ipsilateral spinal cord (ISC) tissues. Consistently, lipopolysaccharide (LPS) exposure also reduced
DUSP8 in murine microglial cells. Adeno-associated virus (AAV)-mediated DUSP8 over-expression was found to considerably ameliorate SNL-induced neuropathic pain in rats. Additionally, neuronal death in the ISC tissues was also attenuated by AAV-
DUSP8 following SNL surgery. Moreover, SNL-triggered neuroinflammation and microglial activation were also mitigated upon DUSP8 over-expression by suppressing nuclear factor κB (NF-κB) signaling, which were validated in LPS-exposed microglial cells. Importantly, our in vitro experiments indicated that inflammatory response in microglial cells contributed to neuron death, and such effect could also be ameliorated by DUSP8 over-expression. Notably, we found that DUSP8 directly interacted with transforming growth factor β activated kinase-1 (TAK1) in microglial cells. Both SNL and LPS led to the activation of TAK1/p38/JNK1/2 signaling, whereas being strongly abolished by DUSP8. Intriguingly, TAK1 blockage significantly diminished LPS-induced inflammation and neuron death, whereas being accelerated by DUSP8 knockdown, further indicating that
DUSP8-ameliorated neuropathic pain was largely TAK1-dependent. Together, all our findings revealed that DUSP8/TAK1 signaling may be a potential target for neuropathic pain alleviation.