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

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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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References

  1. Stadelmann C, Wegner C, Brück W (2011) Inflammation, demyelination, and degeneration—recent insights from MS pathology. Biochim Biophys Acta - Mol Basis Dis 1812:275–282

    Article  CAS  Google Scholar 

  2. Meuth SG, Gobel K, Wiendl H (2012) Immune therapy of multiple sclerosis—future strategies. Curr Pharm Des 18:4489–4497

    Article  CAS  PubMed  Google Scholar 

  3. Kipp M, Clarner T, Dang J et al (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol (Berl) 118:723–736

    Article  Google Scholar 

  4. Skripuletz T, Gudi V, Hackstette D, Stangel M (2011) De- and remyelination in the CNS white and grey matter induced by cuprizone: the old, the new, and the unexpected. Histol Histopathol 26:1585–1597

    CAS  PubMed  Google Scholar 

  5. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol Zurich Switz 11:107–116

    Article  CAS  Google Scholar 

  6. Campbell IL, Hofer MJ, Pagenstecher A (2010) Transgenic models for cytokine-induced neurological disease. Biochim Biophys Acta - Mol Basis Dis 1802:903–917

    Article  CAS  Google Scholar 

  7. Curtis MM, Way SS (2009) Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 126:177–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rouvier E, Luciani M, Mattei M et al (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a Herpesvirus saimiri gene. J Immunol 150:5445–5456

    CAS  PubMed  Google Scholar 

  9. Zimmermann J, Krauthausen M, Hofer MJ et al (2013) CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia. PLoS One 8:e57307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006) Signals mediated by transforming growth factor-[beta] initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7:1151–1156

    Article  CAS  PubMed  Google Scholar 

  11. Komiyama Y, Nakae S, Matsuki T et al (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573

    Article  CAS  PubMed  Google Scholar 

  12. Hofstetter HH, Ibrahim SM, Koczan D et al (2005) Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 237:123–130

    Article  CAS  PubMed  Google Scholar 

  13. Hu Y, Ota N, Peng I et al (2010) IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis. J Immunol 184:4307–4316

    Article  CAS  PubMed  Google Scholar 

  14. Kang Z, Altuntas CZ, Gulen MF et al (2010) Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity 32:414–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kang Z, Wang C, Zepp J et al (2013) Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16:1401–1408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Paxinos G, Franklin BJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego

  17. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  PubMed  Google Scholar 

  18. Skripuletz T, Lindner M, Kotsiari A et al (2008) Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am J Pathol 172:1053–1061

    Article  PubMed  PubMed Central  Google Scholar 

  19. Xu H, Yang H-J, Zhang Y et al (2009) Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci 123:418–429

    Article  CAS  PubMed  Google Scholar 

  20. Zhang H, Zhang Y, Xu H et al (2013) Locomotor activity and anxiety status, but not spatial working memory, are affected in mice after brief exposure to cuprizone. Neurosci Bull 29:633–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Prajeeth CK, Löhr K, Floess S et al (2014) Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun 37:248–259

    Article  CAS  PubMed  Google Scholar 

  22. Sarma JD, Ciric B, Marek R et al (2009) Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 6:14

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kawanokuchi J, Shimizu K, Nitta A et al (2008) Production and functions of IL-17 in microglia. J Neuroimmunol 194:54–61

    Article  CAS  PubMed  Google Scholar 

  24. Ge D, You Z (2008) Expression of interleukin-17RC protein in normal human tissues. Int Arch Med 1:19

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang J, Kou J, Lim J-E et al (2016) Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway. Brain Behav Immun 53:84–95

    Article  PubMed  Google Scholar 

  26. Lampron A, Larochelle A, Laflamme N et al (2015) Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 212:481–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tanaka H, Ma J, Tanaka KF, et al. (2009) Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities. J Neurosci:8363–8371

  28. Xu H, Yang H-J, Rose GM, Li X-M (2011) Recovery of behavioral changes and compromised white matter in C57BL/6 mice exposed to cuprizone: effects of antipsychotic drugs. Front Behav Neurosci 5:31

    Article  PubMed  PubMed Central  Google Scholar 

  29. Li H, Zhang Q, Li N et al (2016) Plasma levels of Th17-related cytokines and complement C3 correlated with aggressive behavior in patients with schizophrenia. Psychiatry Res. doi:10.1016/j.psychres.2016.10.061

    PubMed Central  Google Scholar 

  30. Debnath M, Berk M (2014) Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull 40:1412–1421

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kang Z, Liu L, Spangler R et al (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284–8292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Baxi EG, DeBruin J, Tosi DM et al (2015) Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J Neurosci 35:8626–8639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu LP, Belkadi A, Darnall L et al (2010) CXCR2+ neutrophils play an essential role in cuprizone-induced demyelination: relevance to multiple sclerosis. Nat Neurosci 13:319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bénardais K, Kotsiari A, Skuljec J et al (2013) Cuprizone [bis(cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox Res 24:244–250. doi:10.1007/s12640-013-9380-9

    Article  PubMed  Google Scholar 

  35. Fulmer CG, VonDran MW, Stillman AA et al (2014) Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination. J Neurosci 34:8186–8196

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mason JL, Ye P, Suzuki K et al (2000) Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci 20:5703–5708

    CAS  PubMed  Google Scholar 

  37. Pasquini LA, Calatayud CA, Uña ALB et al (2007) The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochem Res 32:279–292

    Article  CAS  PubMed  Google Scholar 

  38. Bologa L (1985) Oligodendrocytes, key cells in myelination and target in demyelinating diseases. J Neurosci Res 14:1–20

    Article  CAS  PubMed  Google Scholar 

  39. Roussel G, Nussbaum JL (1983) Immunohistochemical study with an anti-myelin serum. A marker for all glial cells except “dark” oligodendrocytes. J Neuroimmunol 5:209–226

    Article  CAS  PubMed  Google Scholar 

  40. Martini R, Schachner M (1997) Molecular bases of myelin formation as revealed by investigations on mice deficient in glial cell surface molecules. Glia 19:298–310

    Article  CAS  PubMed  Google Scholar 

  41. Mithen FA, Wood PM, Agrawal HC, Bunge RP (1983) Immunohistochemical study of myelin sheaths formed by oligodendrocytes interacting with dissociated dorsal root ganglion neurons in culture. Brain Res 262:63–69

    Article  CAS  PubMed  Google Scholar 

  42. Matthieu JM (1986) 2′,3′-Cyclic nucleotide 3′-phosphodiesterase in CNS and PNS myelin: two molecular forms. J Neurochem 47:1963

    Article  CAS  PubMed  Google Scholar 

  43. Thompson RJ (1992) 2′,3′-Cyclic nucleotide-3′-phosphohydrolase and signal transduction in central nervous system myelin. Biochem Soc Trans 20:621–626

    Article  CAS  PubMed  Google Scholar 

  44. Plemel JR, Manesh SB, Sparling JS, Tetzlaff W (2013) Myelin inhibits oligodendroglial maturation and regulates oligodendrocytic transcription factor expression. Glia 61:1471–1487

    Article  PubMed  Google Scholar 

  45. Mei F, Wang H, Liu S et al (2013) Stage-specific deletion of Olig2 conveys opposing functions on differentiation and maturation of oligodendrocytes. J Neurosci 33:8454–8462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Paintlia MK, Paintlia AS, Singh AK, Singh I (2011) Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis. J Neurochem 116:508–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ludwin SK, Sternberger NH (1984) An immunohistochemical study of myelin proteins during remyelination in the central nervous system. Acta Neuropathol (Berl) 63:240–248

    Article  CAS  Google Scholar 

  48. Tansey FA, Zhang H, Cammer W (1997) Rapid upregulation of the Pi isoform of glutathione-S-transferase in mouse brains after withdrawal of the neurotoxicant, cuprizone. Mol Chem 31:161–170

    CAS  Google Scholar 

  49. Goldberg J, Daniel M, van Heuvel Y et al (2013) Short-term cuprizone feeding induces selective amino acid deprivation with concomitant activation of an integrated stress response in oligodendrocytes. Cell Mol Neurobiol 33:1087–1098

    Article  CAS  PubMed  Google Scholar 

  50. Kotter MR, Li W-W, Zhao C, Franklin RJM (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332

    Article  CAS  PubMed  Google Scholar 

  51. Skripuletz T, Hackstette D, Bauer K et al (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain 136:147–167

    Article  PubMed  Google Scholar 

  52. Praet J, Guglielmetti C, Berneman Z et al (2014) Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 47:485–505

    Article  CAS  PubMed  Google Scholar 

  53. Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170:1713–1724

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ransohoff RM, Hafler DA, Lucchinetti CF (2015) Multiple sclerosis—a quiet revolution. Nat Rev Neurol 11:134–142

    Article  PubMed  PubMed Central  Google Scholar 

  55. Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R et al (2012) Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II). Rev Neurol 54:734–749

    PubMed  Google Scholar 

  56. Fernández Ó, Álvarez-Cermeño JC, Arroyo-González R et al (2012) Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I). Rev Neurol 54:677–691

    PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany

    Julian Zimmermann, Michael Emrich, Marius Krauthausen, Simon Saxe, Louisa Nitsch & Marcus Müller

  2. Clinical Neurosciences, Department of Neurology, University of Bonn, Bonn, Germany

    Michael T. Heneka

  3. School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia

    Iain L. Campbell

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  1. Julian Zimmermann
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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)

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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)

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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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