Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Immunol. 2011 Nov 1;187(9):4788-99. doi: 10.4049/jimmunol.1004111. Epub 2011 Sep 30.
Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1-expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1-expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.
内质网（ER）应激是一种细胞内的稳态机制，用于细胞适应细胞内和细胞间的变化。此外，ER 应激与炎症途径密切相关。我们假设 ER 应激是神经炎症的一个组成部分，并有助于神经退行性疾病的发展。在多发性硬化症（MS）和非-MS 患者的尸检脑组织标本中，XBP-1 剪接变异体（XBP-1/s）在 MS 大脑中增加（p <0.05），并与内源性人类逆转录病毒-W 包膜转录物的表达相关，该转录物编码糖蛋白 Syncytin-1（p <0.05）。在转染了表达 Syncytin-1 的质粒的原代人胎儿星形胶质细胞中，XBP-1/s、BiP 和 NOS2 被诱导，而 crocin 处理则抑制了这种诱导（p <0.05）。Crocin 还保护了暴露于表达 Syncytin-1 的星形胶质细胞的细胞毒性上清液中的少突胶质细胞（p <0.05）和 NO 介导的少突胶质细胞毒性（p <0.05）。在实验性自身免疫性脑脊髓炎（EAE）中，与健康同窝仔相比，患病脊髓中的 ER 应激基因 XBP-1/s、BiP、PERK 和 CHOP 的转录水平升高（p <0.05），尽管 CHOP 表达与 EAE 疾病表型无关。EAE 诱导后第 7 天开始每天用 crocin 治疗，可抑制脊髓中的 ER 应激和炎症基因表达（p <0.05），同时伴随着髓鞘和轴突密度的保存，以及 T 细胞浸润和巨噬细胞激活的减少。Crocin 治疗也改善了与 EAE 相关的神经行为缺陷（p <0.05）。这些发现强调了致病 ER 应激和免疫途径在神经炎症性疾病中的共同作用，并指出了 crocin 的潜在治疗应用。
