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

Abstract

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.

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Acknowledgements

This study was supported by a grant of the BONFOR program of the Medical Faculty of the University of Bonn.

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Correspondence to Julian Zimmermann.

Electronic Supplementary Material

Supplemental Fig. 6

CNS production of IL-17 has no impact on remyelination 8 days after CPZ withdrawal. PLP immunohistochemistry after complete demyelination for 5 weeks and subsequent remyelination for 8 days displayed a complete remyelination in both GF/IL17 mice and wild-type littermate controls (n = 3/per genotype). (GIF 67.4 kb)

High Resolution Image (TIFF 905 kb)

Supplemental Fig. 7

CNS production of IL-17 during CPZ-induced demyelination does not affect production of proinflammatory cytokines or chemokines. Real time PCR revealed an induction of the cytokines IL-6, IL-1β, the chemokines CXCL1, CCL2, CCL3 and the CSF-1-receptor during CPZ treatment. A comparison between GF/IL17 mice and wild-type littermate controls could not detect any significant differences between groups. (GIF 67.6 kb)

High Resolution Image (TIFF 256 kb)

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Zimmermann, J., Emrich, M., Krauthausen, M. et al. IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination. Mol Neurobiol 55, 946–957 (2018). https://doi.org/10.1007/s12035-016-0368-3

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Keywords

  • Interleukin-17
  • Cuprizone
  • Demyelination
  • Granulocytes
  • Myelin
  • Cytokines