Brain gray matter astroglia-specific connexin 43 ablation attenuates spinal cord inflammatory demyelination

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Demyelination is accompanied by activation of astroglia in acute and chronic MS lesions [1]. Acute MS lesions contain numerous hypertrophic astrocytes that secrete multiple proinflammatory cytokines and chemokines, thereby augmenting neuroinflammation, as well as various growth factors that promote oligodendrocytes to form myelin by influencing oligodendrocyte progenitor cells [2, 3]. In chronic MS lesions, astrogliotic scars are formed, which may prevent axonal growth and tissue repair. However, the ablation of proliferating astroglia exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS that is associated with a massive infiltration of macrophages and T cells [4], which indicates critical roles of astroglia in preventing the expansion of neuroinflammation. Therefore, astroglia exert proinflammatory and neuroprotective effects on MS pathology.

We and others reported marked alterations of glial connexins (Cxs) in autopsied MS lesions. A previous study reported the loss of astroglial Cxs 30 and 43 and oligodendroglial Cxs 32 and 47 in acute plaques, and unchanged Cxs 32 and 47, and extensively upregulated Cx43 reflecting astrogliosis in chronic plaques [5, 6]. Cxs, transmembrane proteins that form gap junction (GJ) channels that allow the intercellular exchange of ions, secondary messengers, and energy sources [7, 8], have crucial roles in maintaining metabolic homeostasis of the brain [9, 10]. Thus, the aberrant expression of glial Cxs in MS lesions might impair neural functions in MS [5, 6]. Moreover, we found that the conditional knockout of oligodendroglial Cx47 exacerbated acute and chronic EAE [11], whereas the knockout of astroglial Cx30 attenuated chronic, but not acute, EAE [12]. These findings underscore the importance of glial Cxs in regulating neuroinflammation in addition to their metabolic functions [13,14,15]. Cx47 forms oligodendroglia-astroglia GJ channels with Cx43 whereas the loss of Cx47 leads to increased Cx43 hemichannels that secrete various bioactive molecules, including proinflammatory cytokines and chemokines [16, 17].

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Interestingly, the in vivo imaging of activated astroglia by bioluminescence technology revealed that brain astroglia activated prior to the onset of EAE are detectable as early as 3 days post-immunization (dpi) and increase in number until the onset of acute EAE [18]. However, the role of brain astroglia activated by spinal cord inflammation before the onset of EAE is unknown. Therefore, we characterized the effects of brain astroglia on spinal cord inflammation in EAE. Here, we focused on Cx43 expressed on cortical astroglia because Cx43 has a critical role in controlling the CNS inflammatory milieu [17]. By using the glutamate aspartate transporter (GLAST)+ astroglia-specific inducible conditional knockout of Cx43 in mice, which specifically ablates Cx43 in brain gray matter astroglia [19], we demonstrated the remote proinflammatory effects of brain cortical astroglia on spinal cord inflammatory demyelination involving Cx43.

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