Neuromyelitis optica, a rare neuroinflammatory demyelinating disease of the CNS, is characterized by the presence of specific pathogenic autoantibodies directed against the astrocytic water channel aquaporin 4 (AQP4) and is now considered as an astrocytopathy associated either with complement-dependent astrocyte death or with astrocyte dysfunction. However, the link between astrocyte dysfunction and demyelination remains unclear. We propose glial intercellular communication, supported by connexin hemichannels and gap junctions, to be involved in demyelination process in neuromyelitis optica. Using mature myelinated cultures, we demonstrate that a treatment of 1 h to 48 h with immunoglobulins purified from patients with neuromyelitis optica (NMO-IgG) is responsible for a complement independent demyelination, compared to healthy donors’ immunoglobulins (P < 0.001). In parallel, patients’ immunoglobulins induce an alteration of connexin expression characterized by a rapid loss of astrocytic connexins at the membrane followed by an increased size of gap junction plaques (+60%; P < 0.01). This was co-observed with connexin dysfunction with gap junction disruption (−57%; P < 0.001) and increased hemichannel opening (+17%; P < 0.001), associated with glutamate release. Blocking connexin 43 hemichannels with a specific peptide was able to prevent demyelination in co-treatment with patients compared to healthy donors’ immunoglobulins. By contrast, the blockade of connexin 43 gap junctions with another peptide was detrimental for myelin (myelin density −48%; P < 0.001). Overall, our results suggest that dysregulation of connexins would play a pathogenetic role in neuromyelitis optica. The further identification of mechanisms leading to connexin dysfunction and soluble factors implicated, would provide interesting therapeutic strategies for demyelinating disorders.

中文翻译：

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视神经脊髓炎中的连接蛋白：星形细胞病变与脱髓鞘之间的联系。

视神经脊髓炎是一种罕见的中枢神经系统神经炎性脱髓鞘疾病，其特征是存在针对星形细胞水通道水通道蛋白4（AQP4）的特异性致病性自身抗体，目前被认为是与补体依赖性星形胶质细胞死亡或星形胶质细胞相关的星形细胞病变功能障碍。但是，星形胶质细胞功能障碍和脱髓鞘之间的联系仍然不清楚。我们建议神经胶质细胞间通讯，连接蛋白半通道和间隙连接的支持下，参与视神经脊髓炎的脱髓鞘过程。使用成熟的髓鞘培养物，我们证明用视神经脊髓炎患者（NMO-IgG）纯化的免疫球蛋白治疗1小时至48小时可引起补体依赖性脱髓鞘，P <  0.001）。同时，患者的免疫球蛋白诱导连接蛋白表达改变，其特征是膜上星形细胞连接蛋白迅速丢失，然后间隙连接斑块大小增加（+ 60％；P <  0.01）。这与伴有缝隙连接破坏的连接蛋白功能障碍（-57％；P <  0.001）和半通道开放增加（+ 17％；P <  0.001）共同观察到，与谷氨酸释放有关。与健康供体的免疫球蛋白相比，用特定的肽阻断连接蛋白43半通道能够预防与患者共治疗的脱髓鞘。相比之下，连接蛋白43间隙连接与另一种肽的阻断对髓磷脂是有害的（髓磷脂密度为-48％；P < 0.001）。总的来说，我们的结果表明连接蛋白的失调将在视神经脊髓炎中发挥致病作用。导致连接蛋白功能障碍和涉及的可溶性因子的机制的进一步鉴定，将为脱髓鞘疾病提供有趣的治疗策略。