Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination

Abstract

Recent evidence suggests that astrocytes play an important role in regulating de- and remyelination in multiple sclerosis. The role of astrocytes is controversial, and both beneficial as well as detrimental effects are being discussed. We performed loss-of-function studies based on astrocyte depletion in a cuprizone-induced rodent model of demyelination. This led to strong astrogliosis accompanied by microgliosis and demyelination in C57BL/6 wild-type mice. Ablation of astrocytes in glial fibrillary acidic protein-thymidine kinase transgenic mice was associated with a failure of damaged myelin removal and a consecutive delay in remyelination. Despite oligodendrocyte death, myelin was still present, but ultrastructual investigations showed that the myelin structure was loosened and this damaged myelin did not protect axons. These alterations were associated with a decrease in microglial activation. Thus, our results show that astrocyte loss does not prevent myelin damage, but clearance of damaged myelin through recruitment of microglia is impaired. Further studies suggest that this process is regulated by the chemokine CXCL10. As a consequence of the delayed removal of myelin debris, remyelination and oligodendrocyte precursor cell proliferation were impaired. Experiments omitting the influence of myelin debris demonstrated an additional beneficial effect of astrocytes on oligodendrocyte regeneration during remyelination. In conclusion, these data demonstrate for the first time in vivo that astrocytes provide the signal environment that forms the basis for the recruitment of microglia to clear myelin debris, a process required for subsequent repair mechanisms. This is of great importance to understanding regenerative processes in demyelinating diseases such as multiple sclerosis.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…At W4 of CPZ, proinflammatory MPs in the corpus callosum express the phagocytic marker CD11b and are responsible for the phagocytosis of myelin debris (53,54). This supportive action of MPs is an essential step for subsequent remyelination at W6 and W6 + W6 recovery (49,55). Indeed, directing MPs toward an antiinflammatory phenotype before and during the first weeks of CPZ diet prevents in part oligodendrocyte cell death, demyelination, and astrogliosis (52,56).…”

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination

“…For most of the studies exploring mechanisms of demyelination, remyelination and axonal damage in the cuprizone mouse model, time intervals of weeks or months were used (Gudi et al, 2009; Lindner, Fokuhl, Linsmeier, Trebst, & Stangel, 2009; Lindner et al, 2008; Skripuletz et al, 2013; Stidworthy, Genoud, Suter, Mantei, & Franklin, 2003). In the present study the very short time intervals of only days enabled a detailed analysis of early remyelination and axonal damage.…”

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

“…Source of CXCL10 in the cuprizone model We were recently able to demonstrate that CXCL10, derived from activated astrocytes, orchestrates myelin repair after cuprizone-induced demyelination (52). In this study, we further investigated the source of CXCL10 during initial oligodendrocyte apoptosis.…”

“…The pivotal function of CXCL10-expressing astrocytes for remyelination processes in this model has recently been highlighted (52). To characterize the source of CXCL10 during initial microglia activation, we performed IHC double labeling of GFAP and CXCL10.…”

“…The cuprizone model is a frequently used tool to study regenerative processes in the brain, that is, remyelination (26,35,52,58,59). These studies are many times reported in the context of the demyelinating disorder MS; however, principal mechanisms underlying reappearance of new myelinating oligodendrocytes are most likely relevant for a broad spectrum of diseases in which myelination is disturbed.…”