当前位置: X-MOL 学术Neurotherapeutics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting the RNA-Binding Protein HuR Alleviates Neuroinflammation in Experimental Autoimmune Encephalomyelitis: Potential Therapy for Multiple Sclerosis
Neurotherapeutics ( IF 5.7 ) Pub Date : 2020-11-16 , DOI: 10.1007/s13311-020-00958-8
Vittoria Borgonetti 1 , Maria Domenica Sanna 1 , Laura Lucarini 1 , Nicoletta Galeotti 1
Affiliation  

Multiple sclerosis (MS) is a chronic autoimmune inflammatory and neurodegenerative disease of the central nervous system characterized by demyelination, axonal loss, and motor dysfunction. Activated microglia are associated with the destruction of myelin in the CNS. Activated microglia produce cytokines and proinflammatory factors, favoring neuroinflammation, myelin damage, and neuronal loss, and it is thought to be involved in the disease pathogenesis. The present study investigated the role of post-transcriptional regulation of gene expression on the neuroinflammation related to experimental autoimmune encephalomyelitis (EAE) in mice, by focusing on HuR, an RNA-binding protein involved in inflammatory and immune phenomena. Spinal cord sections of EAE mice showed an increased HuR immunostaining that was abundantly detected in the cytoplasm of activated microglia, a pattern associated with its increased activity. Intrathecal administration of an anti-HuR antisense oligonucleotide (ASO) decreased the proinflammatory activated microglia, inflammatory infiltrates, and the expression of the proinflammatory cytokines IL-1β, TNF-α, and IL-17, and inhibited the activation of the NF-κB pathway. The beneficial effect of anti-HuR ASO in EAE mice corresponded also to a decreased permeability of the blood–brain barrier. EAE mice showed a reduced spinal CD206 immunostaining that was restored by anti-HuR ASO, indicating that HuR silencing promotes a shift to the anti-inflammatory and regenerative microglia phenotype. Mice that received anti-HuR ASO exhibited improved EAE-related motor dysfunction, pain hypersensitivity, and body weight loss. Targeting HuR might represent an innovative and promising perspective to control neurological disturbances in MS patients.



中文翻译:

靶向 RNA 结合蛋白 HuR 可减轻实验性自身免疫性脑脊髓炎中的神经炎症:多发性硬化症的潜在治疗方法

多发性硬化症 (MS) 是一种中枢神经系统的慢性自身免疫性炎症和神经退行性疾病,其特征是脱髓鞘、轴突缺失和运动功能障碍。活化的小胶质细胞与中枢神经系统髓磷脂的破坏有关。活化的小胶质细胞产生细胞因子和促炎因子,有利于神经炎症、髓鞘损伤和神经元丢失,并被认为与疾病发病机制有关。本研究通过关注 HuR(一种参与炎症和免疫现象的 RNA 结合蛋白)研究了基因表达的转录后调控对小鼠实验性自身免疫性脑脊髓炎 (EAE) 相关的神经炎症的作用。EAE 小鼠的脊髓切片显示出增加的 HuR 免疫染色,这种染色在活化的小胶质细胞的细胞质中大量检测到,这种模式与其活性增加有关。鞘内注射抗 HuR 反义寡核苷酸 (ASO) 可减少促炎激活的小胶质细胞、炎症浸润和促炎细胞因子 IL-1β、TNF-α 和 IL-17 的表达,并抑制 NF-κB 的活化途径。EAE 小鼠中抗 HuR ASO 的有益作用也对应于血脑屏障通透性降低。EAE 小鼠表现出减少的脊髓 CD206 免疫染色,由抗 HuR ASO 恢复,表明 HuR 沉默促进了向抗炎和再生小胶质细胞表型的转变。接受抗 HuR ASO 的小鼠表现出改善的 EAE 相关运动功能障碍、疼痛过敏和体重减轻。靶向 HuR 可能代表了一种控制 MS 患者神经障碍的创新和有前景的观点。

更新日期:2020-11-17
down
wechat
bug