Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China.
Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China.
Int Immunopharmacol. 2022 Dec;113(Pt A):109284. doi: 10.1016/j.intimp.2022.109284. Epub 2022 Oct 21.
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.
神经损伤诱导的神经病理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，其潜在的分子机制尚不清楚。双特异性磷酸酶 8（DUSP8）可以介导许多细胞事件，但它是否参与神经病理性疼痛尚不清楚。在这项研究中，我们发现大鼠脊神经结扎（SNL）手术显著降低了同侧脊髓（ISC）组织中 DUSP8 的表达水平。同样，脂多糖（LPS）暴露也降低了小鼠小胶质细胞中的 DUSP8。发现腺相关病毒（AAV）介导的 DUSP8 过表达可显著改善大鼠 SNL 诱导的神经病理性疼痛。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，DUSP8 过表达减轻了 SNL 触发的神经炎症和小胶质细胞激活，这在 LPS 暴露的小胶质细胞中得到了验证。重要的是，我们的体外实验表明，小胶质细胞中的炎症反应导致神经元死亡，这种效应也可以通过 DUSP8 的过表达得到改善。值得注意的是，我们发现 DUSP8 可在小胶质细胞中与转化生长因子β激活激酶 1（TAK1）直接相互作用。SNL 和 LPS 均导致 TAK1/p38/JNK1/2 信号通路的激活，而 DUSP8 则强烈抑制该信号通路。有趣的是，TAK1 阻断显著减少了 LPS 诱导的炎症和神经元死亡，而 DUSP8 敲低则加速了这一过程，进一步表明 DUSP8 减轻神经病理性疼痛在很大程度上依赖于 TAK1。总之，我们的所有发现表明，DUSP8/TAK1 信号可能是缓解神经病理性疼痛的一个潜在靶点。
