PMID- 36279673 OWN - NLM STAT- MEDLINE DCOM- 20221205 LR - 20221205 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 113 IP - Pt A DP - 2022 Dec TI - DUSP8/TAK1 signaling mediates neuropathic pain through regulating neuroinflammation and neuron death in a spinal nerve ligation (SNL) rat model. PG - 109284 LID - S1567-5769(22)00768-8 [pii] LID - 10.1016/j.intimp.2022.109284 [doi] AB - 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 kappaB (NF-kappaB) 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 beta 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. CI - Copyright (c) 2022. Published by Elsevier B.V. FAU - Liao, Chenlong AU - Liao C AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Zhou, Han AU - Zhou H AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Chen, Hongjin AU - Chen H AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Cheng, Guo AU - Cheng G AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Li, Shuo AU - Li S AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Ma, Fukai AU - Ma F AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Yang, Xiaosheng AU - Yang X AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Xie, Bingran AU - Xie B AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. FAU - Zhang, Wenchuan AU - Zhang W AD - Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China. Electronic address: zhangwench88@sjtu.edu.cn. LA - eng PT - Journal Article DEP - 20221021 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - EC 3.1.3.48 (Dual-Specificity Phosphatases) RN - 0 (Lipopolysaccharides) RN - EC 2.7.11.25 (MAP kinase kinase kinase 7) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) SB - IM MH - Animals MH - Mice MH - Rats MH - *Dual-Specificity Phosphatases/metabolism MH - Hyperalgesia/metabolism MH - Inflammation/metabolism MH - Ligation MH - Lipopolysaccharides MH - *Neuralgia/metabolism MH - Neuroinflammatory Diseases MH - Neurons/metabolism MH - Rats, Sprague-Dawley MH - Spinal Cord MH - Spinal Nerves/surgery MH - *MAP Kinase Kinase Kinases/metabolism OTO - NOTNLM OT - DUSP8 OT - Neuroinflammation OT - Neuronal death OT - Neuropathic pain OT - TAK1 COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/10/25 06:00 MHDA- 2022/12/03 06:00 CRDT- 2022/10/24 18:18 PHST- 2021/09/23 00:00 [received] PHST- 2022/09/01 00:00 [revised] PHST- 2022/09/22 00:00 [accepted] PHST- 2022/10/25 06:00 [pubmed] PHST- 2022/12/03 06:00 [medline] PHST- 2022/10/24 18:18 [entrez] AID - S1567-5769(22)00768-8 [pii] AID - 10.1016/j.intimp.2022.109284 [doi] PST - ppublish SO - Int Immunopharmacol. 2022 Dec;113(Pt A):109284. doi: 10.1016/j.intimp.2022.109284. Epub 2022 Oct 21.