[en] [en] BACKGROUND: The functional state of glial cells, like astrocytes and microglia, critically modulates the course of neuroinflammatory and neurodegenerative diseases and can have both detrimental and beneficial effects. Glial cell function is tightly controlled by cellular interactions in which cytokines are important messengers. Recent studies provide evidence that in particular chemokines are important modulators of glial cell function. During the course of CNS diseases like multiple sclerosis or Alzheimer's disease, and in the corresponding animal models, the chemokines CXCL9 and CXCL10 are abundantly expressed at sites of glial activation, arguing for an important role of these chemokines and their corresponding receptor CXCR3 in glial activation. To clarify the role of this chemokine system in glial cell activation, we characterized the impact of CXCR3 on glial activation in a model of toxic demyelination in which glial activation without a prominent influx of hematogenous cells is prototypical.
METHODS: We investigated the impact of CXCR3 on cuprizone-induced demyelination, comparing CXCR3-deficient mice with wild type controls. The clinical course during cuprizone feeding was documented for five weeks and for the subsequent four days withdrawal of the cuprizone diet (5.5 weeks). Glial activation was characterized using histological, histomorphometric and phenotypic analysis. Molecular analysis for (de)myelination and neuroinflammation was applied to characterize the effect of cuprizone on CXCR3-deficient mice and control animals.
RESULTS: CXCR3-deficient mice displayed a milder clinical course during cuprizone feeding and a more rapid body weight recovery after offset of diet. In the CNS, CXCR3 deficiency significantly attenuated the accumulation and activation of microglia and astrocytes. Moreover, a deficiency of CXCR3 reduced the expression of the microglial activation markers CD45 and CD11b. Compared to controls, we observed a vast reduction of RNA levels for proinflammatory cytokines and chemokines like Ccl2, Cxcl10, Tnf and Il6 within the CNS of cuprizone-treated mice. Lastly, CXCR3 deficiency had no major effects on the course of demyelination during cuprizone feeding.
CONCLUSIONS: The CXCR3 chemokine system is critically involved in the intrinsic glial activation during cuprizone-induced demyelination, which significantly modulates the distribution of glial cells and the local cytokine milieu.
Disciplines :
Neurology
Author, co-author :
Krauthausen, Marius ✱; Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str, 25, D-53105 Bonn, Germany. marius.krauthausen@ukb.uni-bonn.de
Saxe, Simon ✱; Department of Neurology, Universitätsklinikum Bonn, D-53105 Bonn, Germany
Zimmermann, Julian; Department of Neurology, Universitätsklinikum Bonn, D-53105 Bonn, Germany
Emrich, Michael; Department of Neurology, Universitätsklinikum Bonn, D-53105 Bonn, Germany
HENEKA, Michael ; Department of Neurology, Universitätsklinikum Bonn, D-53105 Bonn, Germany
Müller, Marcus; Department of Neurology, Universitätsklinikum Bonn, D-53105 Bonn, Germany
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
CXCR3 modulates glial accumulation and activation in cuprizone-induced demyelination of the central nervous system.
Publication date :
16 June 2014
Journal title :
Journal of Neuroinflammation
eISSN :
1742-2094
Publisher :
BioMed Central Ltd., England
Volume :
11
Issue :
1
Pages :
109
Peer reviewed :
Peer Reviewed verified by ORBi
Funding text :
The authors thank Marco Hessler and Carina Folger for expert technical assistance. Iain L. Campbell, Daniel Getts and Martin Stangel are gratefully acknowledged for fruitful discussions. Supported by the Deutsche Forschungsgemeinschaft (KFO177) and the BONFOR-programme of the University of Bonn, Germany.
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