Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Av Almansa 14, Albacete 02006, Spain.
Glia. 2011 Jun;59(6):959-72. doi: 10.1002/glia.21168. Epub 2011 Mar 31.
Selenoprotein S (SelS) is an endoplasmic reticulum (ER)-resident protein involved in the unfolded protein response. Besides reducing ER-stress, SelS attenuates inflammation by decreasing pro-inflammatory cytokines. We have recently shown that SelS is responsive to ischemia in cultured astrocytes. To check the possible association of SelS with astrocyte activation, here we investigate the expression of SelS in two models of brain injury: kainic acid (KA) induced excitotoxicity and cortical mechanical lesion. The regulation of SelS and its functional consequences for neuroinflammation, ER-stress, and cell survival were further analyzed using cultured astrocytes from mouse and human. According to our immunofluorescence analysis, SelS expression is prominent in neurons and hardly detectable in astrocytes from control mice. However, brain injury intensely upregulates SelS, specifically in reactive astrocytes. SelS induction by KA was evident at 12 h and faded out after reaching maximum levels at 3-4 days. Analysis of mRNA and protein expression in cultured astrocytes showed SelS upregulation by inflammatory stimuli as well as ER-stress inducers. In turn, siRNA-mediated SelS silencing combined with adenoviral overexpression assays demonstrated that SelS reduces ER-stress markers CHOP and spliced XBP-1, as well as inflammatory cytokines IL-1β and IL-6 in stimulated astrocytes. SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli. Conversely, SelS suppression compromised astrocyte viability. In summary, our results reveal the upregulation of SelS expression in reactive astrocytes, as well as a new protective role for SelS against inflammation and ER-stress that can be relevant to astrocyte function in the context of inflammatory neuropathologies.
硒蛋白 S（SelS）是一种内质网（ER）驻留蛋白，参与未折叠蛋白反应。除了减轻 ER 应激外，SelS 通过减少促炎细胞因子来减轻炎症。我们最近表明，SelS 对培养的星形胶质细胞中的缺血有反应。为了检查 SelS 与星形胶质细胞激活的可能关联，我们在此研究了两种脑损伤模型中的 SelS 表达：海人酸（KA）诱导的兴奋性毒性和皮质机械损伤。使用来自小鼠和人类的培养星形胶质细胞进一步分析了 SelS 的调节及其对神经炎症、ER 应激和细胞存活的功能后果。根据我们的免疫荧光分析，SelS 表达在神经元中很明显，在对照小鼠的星形胶质细胞中几乎检测不到。然而，脑损伤强烈地上调 SelS，特别是在反应性星形胶质细胞中。KA 诱导的 SelS 诱导在 12 小时时明显，并在 3-4 天时达到最大水平后消失。在培养的星形胶质细胞中分析 mRNA 和蛋白质表达表明，炎症刺激以及 ER 应激诱导剂上调 SelS。反过来，siRNA 介导的 SelS 沉默结合腺病毒过表达测定表明，SelS 减少刺激星形胶质细胞中的 ER 应激标志物 CHOP 和剪接 XBP-1 以及炎性细胞因子 IL-1β 和 IL-6。SelS 过表达增加了星形胶质细胞对 ER 应激和炎症刺激的抵抗力。相反，SelS 抑制使星形胶质细胞活力受损。总之，我们的结果揭示了反应性星形胶质细胞中 SelS 表达的上调，以及 SelS 对抗炎症和 ER 应激的新保护作用，这可能与炎症性神经病理学中星形胶质细胞的功能有关。
