Abstract
BackgroundThe 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.MethodsWe 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.ResultsCXCR3-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.ConclusionsThe 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.
Highlights
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
Recent studies suggest that the chemokine receptor CXCR3 and the corresponding chemokine ligands CXCL9, CXCL10 and CXCL11 are expressed during CNS diseases and modulate glial functions like migration of microglia or cytokine synthesis [17,18,19,20,21,22,23,24,25,26]
A rapid drop of body weight was detectable after the first week of cuprizone feeding, when the body mass of wild type (WT) mice was reduced to 80.4 ± 0.9%, whereas in CXCR3-/mice dropped to 90.8 ± 1.9% (Figure 1; ***P
Summary
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 cells are key participators during pathological changes within the diseased brain [7,8,9,10] Both microglia and astrocytes can be rapidly activated through mechanisms like pattern recognition receptors detecting infectious and endogenous danger signals [7,11,12,13,14,15,16]. Recent studies suggest that the chemokine receptor CXCR3 and the corresponding chemokine ligands CXCL9, CXCL10 and CXCL11 are expressed during CNS diseases and modulate glial functions like migration of microglia or cytokine synthesis [17,18,19,20,21,22,23,24,25,26]
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