Department of Neurology and Rehabilitation, University of Illinois at Chicago, United States.
The Center for Molecular Medicine and Genetics, United States.
J Neuroimmunol. 2018 May 15;318:56-64. doi: 10.1016/j.jneuroim.2018.02.008. Epub 2018 Mar 11.
Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients.
神经调节蛋白 1（NRG1）是一种分化因子，可调节神经胶质细胞的发育、存活、突触形成、轴突胶质相互作用和小胶质细胞激活。我们之前报道，鞘内给予靶向 NRG1 拮抗剂（HBD-S-H4）可减少脊髓疼痛模型和体内神经退行性疾病小鼠模型中的炎症性小胶质细胞激活，表明其可能对神经元炎症和神经元疾病有作用。我们假设中枢神经系统（CNS）中 HBD-S-H4 的表达可以降低实验性自身免疫性脑脊髓炎（EAE）的疾病严重程度，EAE 是一种广泛用于多发性硬化症（MS）的动物模型。在本研究中，我们生成了 tetO-HBD-S-H4，一种在大脑中表达融合蛋白的单转基因（Tg）小鼠系，与性别和年龄匹配的野生型同窝小鼠相比，雄性和雌性小鼠的疾病严重程度均降低。我们还生成了 GFAP-tTA:tetO-HBD-S-H4 双 Tg 小鼠，该融合蛋白在大脑和脊髓中表达，在疾病严重程度降低方面显示出性别差异。在健康小鼠中，CNS 中 HBD-S-H4 的表达不会导致任何明显的神经或其他明显表型。在髓鞘少突胶质细胞糖蛋白（MOG）诱导的 EAE 中，与野生型同窝小鼠和雄性双 Tg 小鼠相比，雌性双 Tg 小鼠的疾病发病时间延迟，疾病严重程度降低。在雄性双 Tg 小鼠中，HBD-S-H4 基因表达水平与疾病严重程度呈负相关，并且与小胶质细胞相关基因的表达增加。总之，神经调节蛋白拮抗剂在大脑和脊髓中的表达可保护雌性小鼠，但不能保护雄性小鼠，这表明 EAE 中 NRG1 与性别差异之间存在复杂的相互作用，这可能与小胶质细胞介导的炎症有关。这项研究为理解疾病病理学的异质性以及靶向男性和女性 MS 患者小胶质细胞激活的治疗潜力提供了重要信息。
