Drug Development, School of Medicine, Trinity College, Dublin, Ireland.
Medical University of Gdańsk, M. Skłodowskiej-Curie 3a, Gdańsk, Poland.
J Neuroinflammation. 2017 Dec 16;14(1):250. doi: 10.1186/s12974-017-1025-0.
The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Abnormal EBI2 signaling is implicated in a range of autoimmune disorders; however, its role in the CNS remains poorly understood.
Here we characterize the role of EBI2 in myelination under normal and pathophysiological conditions using organotypic cerebellar slice cultures and EBI2 knock-out (KO) animals.
We find that MBP expression in brains taken from EBI2 KO mice is delayed compared to those taken from wild type (WT) mice. In agreement with these in vivo findings, we show that antagonism of EBI2 reduces MBP expression in vitro. Importantly, we demonstrate that EBI2 activation attenuates lysolecithin (LPC)-induced demyelination in mouse organotypic slice cultures. Moreover, EBI2 activation also inhibits LPC-mediated release of pro-inflammatory cytokines such as IL6 and IL1β in cerebellar slices.
These results, for the first time, display a role for EBI2 in myelin development and protection from demyelination under pathophysiological conditions and suggest that modulation of this receptor may be beneficial in neuroinflammatory and demyelinating disorders such as multiple sclerosis.
G 蛋白偶联受体 EBI2（Epstein-Barr 病毒诱导基因 2）被 7α，25-二羟胆固醇（7α25HC）激活，在 T 细胞依赖性抗体反应和 B 细胞迁移中发挥作用。异常的 EBI2 信号转导与一系列自身免疫性疾病有关；然而，其在中枢神经系统中的作用仍知之甚少。
在这里，我们使用器官型小脑切片培养物和 EBI2 敲除（KO）动物来表征 EBI2 在正常和病理生理条件下的髓鞘形成作用。
我们发现，与野生型（WT）小鼠相比，EBI2 KO 小鼠大脑中的 MBP 表达延迟。与这些体内发现一致，我们表明 EBI2 拮抗作用可减少体外的 MBP 表达。重要的是，我们证明 EBI2 激活可减轻小鼠器官型切片培养物中溶卵磷脂（LPC）诱导的脱髓鞘。此外，EBI2 激活还可抑制小脑切片中 LPC 介导的促炎细胞因子（如 IL6 和 IL1β）的释放。
这些结果首次显示 EBI2 在病理生理条件下的髓鞘发育和脱髓鞘保护中的作用，并表明该受体的调节可能有益于神经炎症和脱髓鞘疾病，如多发性硬化症。
