Kamarehei Maryam, Pejman Sina, Kaboudanian Ardestani Sussan, Zahednasab Hamid, Firouzi Masoumeh, Harirchian Mohammad Hossein
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Int Immunopharmacol. 2020 Mar 12;82:106286. doi: 10.1016/j.intimp.2020.106286.
Endoplasmic reticulum (ER) stress is strictly linked to neuroinflammation and involves in the development of neurodegenerative disorders. Protein disulfide isomerase (PDI) is an enzyme that catalyzes formation and isomerization of disulfide bonds and also acts as a chaperone that survives the cells against cell death by removal of misfolded proteins. Our previous work revealed that PDI is explicitly upregulated in response to myelin oligodendrocyte glycoprotein (MOG)-induced ER stress in the brain of experimental autoimmune encephalomyelitis (EAE) mice. The significance of overexpression of PDI in the apoptosis of neural cells prompted us to study the effect of CCF642, efficient inhibitor of PDI, in the recovery of EAE clinical symptoms. Using this in vivo model, we characterized the ability of CCF642 to decrease the expression of ER stress markers and neuroinflammation in the hippocampus of EAE mice. Our observations suggested that CCF642 administration attenuates EAE clinical symptomsand the expression of ER stress-related proteins. Further, it suppressed the inflammatory infiltration of CD4 + T cells and the activation of hippocampus-resident microglia and Th17 cells. We reported here that the inhibition of PDI protected EAE mice against neuronal apoptosis induced by prolonged ER stress and resulted in neuroprotection.
内质网（ER）应激与神经炎症密切相关，并参与神经退行性疾病的发展。蛋白质二硫键异构酶（PDI）是一种催化二硫键形成和异构化的酶，还作为伴侣蛋白，通过清除错误折叠的蛋白质使细胞免于细胞死亡。我们之前的研究表明，在实验性自身免疫性脑脊髓炎（EAE）小鼠的大脑中，PDI在髓鞘少突胶质细胞糖蛋白（MOG）诱导的内质网应激反应中明显上调。PDI过表达在神经细胞凋亡中的意义促使我们研究PDI高效抑制剂CCF642对EAE临床症状恢复的影响。利用这个体内模型，我们表征了CCF642降低EAE小鼠海马体中内质网应激标志物表达和神经炎症的能力。我们的观察结果表明，给予CCF642可减轻EAE临床症状以及内质网应激相关蛋白的表达。此外，它还抑制了CD4 + T细胞的炎性浸润以及海马体驻留小胶质细胞和Th17细胞的活化。我们在此报告，抑制PDI可保护EAE小鼠免受长时间内质网应激诱导的神经元凋亡，并产生神经保护作用。
