Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation
Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation
复制标题
星形胶质细胞中连接蛋白 43 缺失通过调节局部炎症促进中枢神经系统髓鞘再生
作者：
Li, Tao;Niu, Jianqin;Xiao, Lan
作为中枢神经系统(CNS)中含量最丰富的缝隙连接蛋白，星形胶质细胞连接蛋白43(Cx43)维持星形胶质细胞网络的动态平衡，影响少突胶质细胞的发育，参与中枢神经系统的病理和损伤进展。然而，它在髓鞘再生中的作用还没有完全被了解。为了解决这个问题，我们使用了星形胶质细胞特异性Cx43条件性基因敲除(Cx43 CKO)小鼠，这些小鼠是通过使用hGFAP-cre启动子产生的，与携带Cx43等位基因的小鼠相结合，这些小鼠受到溶血磷脂的影响，以诱导脱髓鞘。我们发现Cx43 CKO小鼠和非Cx43 CKO小鼠的胼胝体脱髓鞘无显著差异，而Cx43 CKO小鼠的再髓鞘形成过程明显加快。此外，在Cx43 CKO小鼠的皮损中发现成熟少突胶质细胞的数量增加，而少突胶质系细胞的数量没有变化。这表明，随着髓鞘再生的进行，星形胶质细胞Cx43的缺失促进了少突胶质前体细胞的分化。在后者的基础上，Cx43 CKO小鼠的神经胶质细胞激活下调，局部炎症得到调节，髓鞘碎片减少。重要的是，口服冰片碱2周后，明显调节了局部炎症并促进了髓鞘再生。冰片碱是一种天然生物碱，可以在不影响缝隙连接通讯的情况下阻断星形胶质细胞的Cx半通道活动。综上所述，这些数据表明，星形细胞Cx43半通道通过促进局部炎症而负面地参与了重新髓鞘形成过程。因此，抑制Cx43半通道功能可能是治疗中枢神经系统脱髓鞘疾病的一种潜在方法。
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.