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Chemogenetic manipulation of microglia inhibits neuroinflammation and neuropathic pain in mice
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-11-01 , DOI: 10.1016/j.bbi.2020.11.030
Min-Hee Yi 1 , Yong U Liu 1 , Kevin Liu 2 , Tingjun Chen 1 , Dale B Bosco 1 , Jiaying Zheng 1 , Manling Xie 1 , Lijun Zhou 3 , Wenchun Qu 4 , Long-Jun Wu 5
Affiliation  

Microglia play an important role in the central sensitization and chronic pain. However, a direct connection between microglial function and pain development in vivo remains incompletely understood. To address this issue, we applied chemogenetic approach by using CX3CR1creER/+:R26LSL-hM4Di/+ transgenic mice to enable expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (Gi DREADD) in microglia. We found that microglial Gi DREADD activation inhibited spinal nerve transection (SNT)-induced microglial reactivity as well as chronic pain in both male and female mice. Gi DREADD activation downregulated the transcription factor interferon regulatory factor 8 (IRF8) and its downstream target pro-inflammatory cytokine interleukin 1 beta (IL-1β). Using in vivo spinal cord recording, we found that activation of microglial Gi DREADD attenuated synaptic transmission following SNT. Our results demonstrate that microglial Gi DREADD reduces neuroinflammation, synaptic function and neuropathic pain after SNT. Thus, chemogenetic approaches provide a potential opportunity for interrogating microglial function and neuropathic pain treatment.

中文翻译:

小胶质细胞的化学遗传学操作抑制小鼠的神经炎症和神经性疼痛

小胶质细胞在中枢敏化和慢性疼痛中起重要作用。然而,小胶质细胞功能与体内疼痛发展之间的直接联系仍不完全清楚。为了解决这个问题,我们通过使用 CX3CR1creER/+:R26LSL-hM4Di/+ 转基因小鼠应用化学遗传学方法,在小胶质细胞中表达由设计药物 (Gi DREADD) 独家激活的抑制性设计受体。我们发现小胶质细胞 Gi DREADD 激活抑制了雄性和雌性小鼠的脊神经横断 (SNT) 诱导的小胶质细胞反应性以及慢性疼痛。Gi DREADD 激活下调转录因子干扰素调节因子 8 (IRF8) 及其下游靶标促炎细胞因子白细胞介素 1 β (IL-1β)。使用体内脊髓记录,我们发现小胶质细胞 Gi DREADD 的激活减弱了 SNT 后的突触传递。我们的研究结果表明,小胶质细胞 Gi DREADD 可减少 SNT 后的神经炎症、突触功能和神经性疼痛。因此,化学遗传学方法为研究小胶质细胞功能和神经性疼痛治疗提供了潜在机会。
更新日期:2020-11-01
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