IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination.

Recent evidence suggests a pivotal role of the proinflammatory cytokine interleukin - 17A (IL-17) in demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS). Nevertheless, it remains unclear if this cytokine exerts direct effects on CNS resident cells during MS or modulates the function of infiltrating immune cells towards a more detrimental phenotype. Here, we investigated the effects of locally produced IL-17 during experimental demyelination of the CNS using the cuprizone (CPZ) model in mice with (GF/IL17) or without transgenic production of IL-17 by astrocytes in the CNS. During early demyelination, GF/IL17 mice demonstrated enhanced activity and decreased anxiety-related behavior in the elevated plus maze suggesting a more severe disease course. Furthermore, in GF/IL17 mice, toxic demyelination was accelerated and synthesis of myelin proteins was reduced. Early demyelination was accompanied by an increased ratio of infiltrating granulocytes in GF/ILl17 mice. The presence of IL-17 during CPZ treatment increased the accumulation of activated microglia and sustained microglial proliferation during myelin loss. Taken together, our results argue for a detrimental role of IL-17 during demyelinating diseases.

CXCR3 modulates glial accumulation and activation in cuprizone-induced demyelination of the central nervous system.

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.

The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability.

The perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms that orchestrate the expression and function of ion channels relevant for pain processing are poorly understood. We demonstrate here a central role of the transcription factor Smad-interacting protein 1 (Sip1/Zfhx1b/Zeb2), a 2-handed zinc finger DNA-binding protein with essential functions in neural crest and forebrain development, in controlling nociceptive neuron excitability and pain sensitivity. Mutant mice lacking 1 Zfhx1b allele displayed decreased thermal pain responses, whereas mechanical pain was unaffected. In parallel, repetitive firing of capsaicin/heat-sensitive nociceptive DRG neurons was markedly impaired. Analysis of the voltage-gated currents underlying repetitive firing revealed a significant increase in persistent sodium currents and a reduction in delayed rectifier potassium currents. Modeling experiments in conjunction with experimental results suggest that these changes cause a depolarization-induced block of action potential propagation past the DRG axon T-junction. These data suggest that Sip1 controls the transduction properties of heat-sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in DRG-neuron voltage-gated ion channels.