title: 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.
authors.affiliation: Department of Neurology, Hannover Medical School, Carl-Neuberg-Str-1, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripuletz
authors.forename: Diane
authors.initials: D
authors.lastname: Hackstette
authors.forename: Katharina
authors.initials: K
authors.lastname: Bauer
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gudi
authors.forename: Refik
authors.initials: R
authors.lastname: Pul
authors.forename: Elke
authors.initials: E
authors.lastname: Voss
authors.forename: Katharina
authors.initials: K
authors.lastname: Berger
authors.forename: Markus
authors.initials: M
authors.lastname: Kipp
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; D003471:Cuprizone