Department of Emergency, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110136, People's Republic of China.
Department of Neurology, the First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province, 110001, People's Republic of China.
Cell Biol Toxicol. 2024 Jul 12;40(1):54. doi: 10.1007/s10565-024-09900-6.
The neuropathic pain with complex networks of neuroinflammatory activation severely limits clinical therapeutic research. TNF receptor-associated factor 6 (TRAF6) is associated with multiple inflammatory diseases. However, there remains confusion about the effects and mechanisms of TRAF6 in neuropathic pain.
A chronic constriction injury (CCI) model was developed to simulate neuralgia in vivo. We overexpressed or knocked down TRAF6 in CCI mice, respectively. Activation of microglia by TRAF6, the inflammatory response, and disease progression were inspected using WB, qRT-PCR, immunofluorescence, flow cytometry, and ELISA assays. Moreover, the mechanism of M1/M2 polarization activation of microglia by TRAF6 was elaborated in BV-2 cells.
TRAF6 was enhanced in the spinal neurons and microglia of the CCI mice model compared with the sham operation group.. Down-regulation of TRAF6 rescued the expression of Iba-1. In response to mechanical and thermal stimulation, PWT and PWL were improved after the knockdown of TRAF6. Decreased levels of pro-inflammatory factors were observed in TRAF6 knockdown groups. Meanwhile, increased microglial M1 markers induced by CCI were limited in mice with TRAF6 knockdown. In addition, TRAF6 overexpression has the precise opposite effect on CCI mice or microglia polarization. We also identifed that TRAF6 activated the c-JUN/NF-kB pathway signaling; the inhibitor of c-JUN/NF-kB could effectively alleviate the neuropathic pain induced by upregulated TRAF6 in the CCI mice model.
In summary, this study indicated that TRAF6 was concerned with neuropathic pain, and targeting the TRAF6/c-JUN/NF-kB pathway may be a prospective target for treating neuropathic pain.
神经病理性疼痛与神经炎症激活的复杂网络严重限制了临床治疗研究。TNF 受体相关因子 6（TRAF6）与多种炎症性疾病有关。然而，TRAF6 在神经病理性疼痛中的作用和机制仍存在争议。
建立慢性缩窄性损伤（CCI）模型模拟体内神经痛。我们分别在 CCI 小鼠中过表达或敲低 TRAF6。通过 WB、qRT-PCR、免疫荧光、流式细胞术和 ELISA 检测 TRAF6 对小胶质细胞的激活、炎症反应和疾病进展。此外，还在 BV-2 细胞中阐述了 TRAF6 对小胶质细胞 M1/M2 极化激活的机制。
与假手术组相比，CCI 小鼠模型的脊髓神经元和小胶质细胞中 TRAF6 表达增强。TRAF6 下调可挽救 Iba-1 的表达。在敲低 TRAF6 后，机械和热刺激的 PWT 和 PWL 得到改善。TRAF6 敲低组促炎因子水平降低。同时，CCI 诱导的小胶质细胞 M1 标志物增加在 TRAF6 敲低的小鼠中受到限制。此外，TRAF6 过表达对 CCI 小鼠或小胶质细胞极化具有精确的相反作用。我们还发现 TRAF6 激活了 c-JUN/NF-kB 通路信号；c-JUN/NF-kB 的抑制剂可有效缓解 CCI 小鼠模型中 TRAF6 上调引起的神经病理性疼痛。
综上所述，本研究表明 TRAF6 与神经病理性疼痛有关，靶向 TRAF6/c-JUN/NF-kB 通路可能是治疗神经病理性疼痛的有前途的靶点。
