Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Neurology, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China.
Front Immunol. 2023 Apr 20;14:1130697. doi: 10.3389/fimmu.2023.1130697. eCollection 2023.
Vagus nerve stimulation (VNS) has a protective effect on neurological recovery in ischaemic stroke. However, its underlying mechanism remains to be clarified. Ubiquitin-specific protease 10 (USP10), a member of the ubiquitin-specific protease family, has been shown to inhibit the activation of the NF-κB signalling pathway. Therefore, this study investigated whether USP10 plays a key role in the protective effect of VNS against ischemic stroke and explore its mechanism.
Ischaemic stroke model was constructed by transient middle cerebral artery occlusion (tMCAO) in mice. VNS was performed at 30 min, 24hr, and 48hr after the establishment of tMCAO model. USP10 expression induced by VNS after tMCAO was measured. LV-shUSP10 was used to establish the model with low expression of USP10 by stereotaxic injection technique. The effects of VNS with or without USP10 silencing on neurological deficits, cerebral infarct volume, NF-κB pathway activation, glial cell activation, and release of pro-inflammation cytokines were assessed.
VNS enhanced the expression of USP10 following tMCAO. VNS ameliorated neurological deficits and reduced cerebral infarct volume, but this effect was inhibited by silencing of USP10. Activation of the NF-κB pathway and the expression of inflammatory cytokines induced by tMCAO were suppressed by VNS. Moreover, VNS promoted the pro-to-anti-inflammatory response of microglia and inhibited activation of astrocytes, while silencing of USP10 prevented the neuroprotective and anti-neuroinflammatory effects of VNS.
USP10 is a potential mediator for VNS to alleviate neurological deficits, neuroinflammation, and glial cell activation in ischaemic stroke by inhibiting NF-κB signalling pathway.
迷走神经刺激（VNS）对缺血性中风后的神经功能恢复具有保护作用。但其潜在机制尚不清楚。泛素特异性蛋白酶 10（USP10）是泛素特异性蛋白酶家族的一员，已被证明能抑制 NF-κB 信号通路的激活。因此，本研究旨在探讨 USP10 是否在 VNS 对缺血性中风的保护作用中起关键作用，并探讨其机制。
采用短暂性大脑中动脉闭塞（tMCAO）构建小鼠缺血性中风模型。在 tMCAO 模型建立后 30min、24h 和 48h 进行 VNS。测量 tMCAO 后 VNS 诱导的 USP10 表达。通过立体定位注射技术，使用 LV-shUSP10 建立 USP10 低表达模型。评估 VNS 联合或不联合 USP10 沉默对神经功能缺损、脑梗死体积、NF-κB 通路激活、胶质细胞激活和促炎细胞因子释放的影响。
VNS 增强了 tMCAO 后 USP10 的表达。VNS 改善了神经功能缺损并减少了脑梗死体积，但这种作用被 USP10 沉默所抑制。tMCAO 诱导的 NF-κB 通路激活和炎症细胞因子表达被 VNS 抑制。此外，VNS 促进了小胶质细胞的前炎症向抗炎反应，并抑制了星形胶质细胞的激活，而 USP10 的沉默阻止了 VNS 的神经保护和抗炎作用。
USP10 是 VNS 通过抑制 NF-κB 信号通路减轻缺血性中风后神经功能缺损、神经炎症和胶质细胞激活的潜在介导物。
