Abstract：
Sevoflurane exposure can result in neurotoxicity especially among children, which remains an important complication after surgery. However, its related mechanisms remain unclear. Here, we investigated the biological roles of SHARPIN in sevoflurane-induced neurotoxicity. As detected by qPCR, Western blotting and immunohistochemical staining, SHARPIN and HMGB1 expression was elevated in sevoflurane-stimulated mice as compared with the control mice. SHARPIN depletion attenuated hippocampus injury, repressed the expression of HMGB1 and M1-like macrophage markers (iNOS, TNF-α, IL-1β, IL-6), but enhanced the expression of M2-like macrophage markers (ARG-1, IL-10). GST pull-down and Co-IP assays demonstrated that SHARPIN directly interacted with HMGB1 to enhance HMGB1 expression in SH-SY5Y cells. The inhibitory effects of SHARPIN silencing on inflammatory reaction and M1-like macrophages were counteracted by HMGB1 overexpression. Finally, SHARPIN-HMGB1 pathway affected neuroinflammation triggered by sevoflurane via modulating macrophage polarization. Collectively, our data suggested that SHARPIN stimulated sevoflurane-induced neurotoxicity via converting M2-like macrophages to M1-like macrophages by enhancing HMGB1 expression. SHARPIN intervention may be a promising therapeutic method to relieve sevoflurane-induced neurotoxicity.
摘要：
七氟醚暴露可导致神经毒性，尤其是在儿童中，这仍然是手术后的重要并发症。然而,其相关机制尚不清楚。这里,我们研究了SHARPIN在七氟醚诱导的神经毒性中的生物学作用.通过qPCR检测，蛋白质印迹和免疫组织化学染色，与对照小鼠相比，七氟醚刺激的小鼠SHARPIN和HMGB1表达升高。SHARPIN耗竭减轻海马损伤，抑制HMGB1和M1样巨噬细胞标志物的表达(iNOS，TNF-α,IL-1β,IL-6),但增强了M2样巨噬细胞标志物（ARG-1，IL-10）的表达。GST下拉和Co-IP测定表明SHARPIN与HMGB1直接相互作用以增强SH-SY5Y细胞中的HMGB1表达。SHARPIN沉默对炎症反应和M1样巨噬细胞的抑制作用被HMGB1过表达所抵消。最后,SHARPIN-HMGB1通路通过调节巨噬细胞极化影响七氟醚引发的神经炎症。总的来说，我们的数据表明,SHARPIN通过增强HMGB1表达,将M2样巨噬细胞转化为M1样巨噬细胞,从而刺激七氟醚诱导的神经毒性.SHARPIN干预可能是减轻七氟醚诱导的神经毒性的有希望的治疗方法。
