CXCL10 triggers early microglial activation in the cuprizone model.

TitleCXCL10 triggers early microglial activation in the cuprizone model.
Publication TypeJournal Article
Year of Publication2015
AuteursClarner, T, Janssen, K, Nellessen, L, Stangel, M, Skripuletz, T, Krauspe, B, Hess, F-M, Denecke, B, Beutner, C, Linnartz-Gerlach, B, Neumann, H, Vallières, L, Amor, S, Ohl, K, Tenbrock, K, Beyer, C, Kipp, M
JournalJ Immunol
Volume194
Issue7
Pagination3400-13
Date Published2015 Apr 01
ISSN1550-6606
KeywordsAnimals, Astrocytes, Cell Movement, Chemokine CXCL10, Chemokines, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Gene Expression, Gene Expression Profiling, Immunohistochemistry, Lactate Dehydrogenases, Mice, Mice, Knockout, Microglia, Oligodendroglia, Phagocytosis, Rats
Abstract

A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

DOI10.4049/jimmunol.1401459
Alternate JournalJ. Immunol.
PubMed ID25725102