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Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation.
Glia ( IF 5.4 ) Pub Date : 2019-12-23 , DOI: 10.1002/glia.23770 Tao Li 1 , Jianqin Niu 1 , Guangdan Yu 1 , Pascal Ezan 2 , Chenju Yi 3 , Xiaorui Wang 1 , Annette Koulakoff 2 , Xing Gao 1 , Xianjun Chen 1 , Juan C Sáez 4, 5 , Christian Giaume 2 , Lan Xiao 1
Glia ( IF 5.4 ) Pub Date : 2019-12-23 , DOI: 10.1002/glia.23770 Tao Li 1 , Jianqin Niu 1 , Guangdan Yu 1 , Pascal Ezan 2 , Chenju Yi 3 , Xiaorui Wang 1 , Annette Koulakoff 2 , Xing Gao 1 , Xianjun Chen 1 , Juan C Sáez 4, 5 , Christian Giaume 2 , Lan Xiao 1
Affiliation
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As the most abundant gap junction protein in the central nervous system (CNS), astrocytic connexin 43 (Cx43) maintains astrocyte network homeostasis, affects oligodendroglial development and participates in CNS pathologies as well as injury progression. However, its role in remyelination is not yet fully understood. To address this issue, we used astrocyte-specific Cx43 conditional knockout (Cx43 cKO) mice generated through the use of a hGFAP-cre promoter, in combination with mice carrying a floxed Cx43 allele that were subjected to lysolecithin so as to induce demyelination. We found no significant difference in the demyelination of the corpus callosum between Cx43 cKO mice and their non-cre littermate controls, while the remyelination process in Cx43 cKO mice was accelerated. Moreover, an increased number of mature oligodendrocytes and an unaltered number of oligodendroglial lineage cells were found in Cx43 cKO mouse lesions. This indicates that oligodendrocyte precursor cell (OPC) differentiation was facilitated by astroglial Cx43 depletion as remyelination progressed. Underlying the latter, there was a down-regulated glial activation and modulated local inflammation as well as a reduction of myelin debris in Cx43 cKO mice. Importantly, 2 weeks of orally administrating boldine, a natural alkaloid that blocks Cx hemichannel activity in astrocytes without affecting gap junctional communication, obviously modulated local inflammation and promoted remyelination. Together, the data suggest that the astrocytic Cx43 hemichannel is negatively involved in the remyelination process by favoring local inflammation. Consequently, inhibiting Cx43 hemichannel functionality may be a potential therapeutic approach for demyelinating diseases in the CNS.
中文翻译：
星形胶质细胞中的连接蛋白 43 缺失通过调节局部炎症促进 CNS 髓鞘再生。
作为中枢神经系统 (CNS) 中最丰富的间隙连接蛋白，星形胶质细胞连接蛋白 43 (Cx43) 维持星形胶质细胞网络稳态，影响少突胶质细胞发育并参与 CNS 病理以及损伤进展。然而，其在髓鞘再生中的作用尚未完全了解。为了解决这个问题，我们使用了通过使用 hGFAP-cre 启动子生成的星形胶质细胞特异性 Cx43 条件性敲除 (Cx43 cKO) 小鼠，并结合携带经过溶血卵磷脂处理以诱导脱髓鞘的 floxed Cx43 等位基因的小鼠。我们发现 Cx43 cKO 小鼠与其非 cre 同窝小鼠的胼胝体脱髓鞘没有显着差异，而 Cx43 cKO 小鼠的髓鞘再生过程加速。此外，在 Cx43 cKO 小鼠病变中发现成熟少突胶质细胞数量增加，少突胶质细胞谱系细胞数量不变。这表明随着髓鞘再生的进展，星形胶质细胞 Cx43 耗竭促进了少突胶质细胞前体细胞 (OPC) 分化。在后者的基础上，Cx43 cKO 小鼠的神经胶质激活下调并调节局部炎症以及髓鞘碎片减少。重要的是，口服博尔丁（一种天然生物碱，可阻断星形胶质细胞中的 Cx 半通道活性而不影响间隙连接通讯）2 周后，明显调节了局部炎症并促进了髓鞘再生。总之，数据表明星形胶质细胞 Cx43 半通道通过有利于局部炎症而负面参与髓鞘再生过程。因此，
更新日期：2019-12-23
中文翻译：
星形胶质细胞中的连接蛋白 43 缺失通过调节局部炎症促进 CNS 髓鞘再生。
作为中枢神经系统 (CNS) 中最丰富的间隙连接蛋白，星形胶质细胞连接蛋白 43 (Cx43) 维持星形胶质细胞网络稳态，影响少突胶质细胞发育并参与 CNS 病理以及损伤进展。然而，其在髓鞘再生中的作用尚未完全了解。为了解决这个问题，我们使用了通过使用 hGFAP-cre 启动子生成的星形胶质细胞特异性 Cx43 条件性敲除 (Cx43 cKO) 小鼠，并结合携带经过溶血卵磷脂处理以诱导脱髓鞘的 floxed Cx43 等位基因的小鼠。我们发现 Cx43 cKO 小鼠与其非 cre 同窝小鼠的胼胝体脱髓鞘没有显着差异，而 Cx43 cKO 小鼠的髓鞘再生过程加速。此外，在 Cx43 cKO 小鼠病变中发现成熟少突胶质细胞数量增加，少突胶质细胞谱系细胞数量不变。这表明随着髓鞘再生的进展，星形胶质细胞 Cx43 耗竭促进了少突胶质细胞前体细胞 (OPC) 分化。在后者的基础上，Cx43 cKO 小鼠的神经胶质激活下调并调节局部炎症以及髓鞘碎片减少。重要的是，口服博尔丁（一种天然生物碱，可阻断星形胶质细胞中的 Cx 半通道活性而不影响间隙连接通讯）2 周后，明显调节了局部炎症并促进了髓鞘再生。总之，数据表明星形胶质细胞 Cx43 半通道通过有利于局部炎症而负面参与髓鞘再生过程。因此，
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