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The voltage-gated proton channel Hv1 promotes microglia-astrocyte communication and neuropathic pain after peripheral nerve injury
Molecular Brain ( IF 3.6 ) Pub Date : 2021-06-28 , DOI: 10.1186/s13041-021-00812-8
Jiyun Peng 1, 2, 3 , Min-Hee Yi 1 , Heejin Jeong 4 , Przemyslaw Peter McEwan 2 , Jiaying Zheng 1 , Gongxiong Wu 5 , Shashank Ganatra 2 , Yi Ren 2, 6 , Jason R Richardson 7 , Seog Bae Oh 4 , Long-Jun Wu 1, 2, 8, 9
Affiliation  

Activation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.

中文翻译:

电压门控质子通道 Hv1 促进周围神经损伤后小胶质细胞-星形胶质细胞通讯和神经性疼痛

脊髓小胶质细胞的激活有助于周围神经损伤引起的神经性疼痛的发展。然而,神经病理性疼痛中小胶质细胞功能的分子机制尚不完全清楚。我们发现在脊髓小胶质细胞中功能性表达的电压门控质子通道 Hv1 在脊髓神经横断 (SNT) 后显着增加。与野生型 (WT) 小鼠相比,脊髓小胶质细胞和缺乏 Hv1 (Hv1 KO) 的小鼠中 Hv1 介导的电压门控质子电流在 SNT 后表现出减弱的疼痛超敏反应。此外,SNT 后 Hv1 KO 小鼠脊髓中活性氧 (ROS) 的小胶质细胞产生和随后的星形胶质细胞活化减少。细胞因子筛选和免疫染色进一步显示,IFN-γ 表达在 Hv1 KO 小鼠的脊髓星形胶质细胞中受到损害。这些结果表明,Hv1 质子通道有助于小胶质细胞 ROS 的产生、星形胶质细胞的活化、IFN-γ 上调以及 SNT 后的后续疼痛超敏反应。该研究表明 Hv1 依赖性小胶质细胞-星形胶质细胞在疼痛超敏反应中的通讯,并将 Hv1 确定为缓解神经性疼痛的新治疗靶点。
更新日期:2021-06-29
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