Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation

Li T.; Niu J.; Yu G.; Ezan P.; Yi C.; Wang X.; Koulakoff A.; Gao, X.; Chen X.; Sáez J.C.; Giaume C.; Xiao L.

Abstract

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.

Más información

Título según WOS: Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation
Título según SCOPUS: Connexin 43 deletion in astrocytes promotes CNS remyelination by modulating local inflammation
Volumen: 68
Número: 6
Fecha de publicación: 2020
Página de inicio: 1201
Página final: 1212
Idioma: English
DOI:

10.1002/glia.23770

Notas: ISI, SCOPUS