Abstract
The cuprizone (CPZ)-induced demyelination is a relatively reproducible animal model and has been extremely useful for identifying the specific cellular and molecular signals that regulate oligodendrocyte survival and efficiency of oligodendrogenesis and remyelination. Here, we reported the temporal and spatial dynamics of astroglial reaction and immune response in CPZ-induced demyelinating model. CPZ did not induce significant microglia and astrocyte reaction after 2 weeks of feeding. After 4–6 weeks of CPZ feeding, microglia and astrocytes were markedly migrated and accumulated in myelin sheath. Simultaneously, the expression of tight junction protein ZO-1 was declined and the infiltration of CD4+IFNγ+ and CD4+IL-17+ T cells was increased in the brain, accompanied by increased production of IFN-γ and IL-17 in the extract of brain. However, the levels of IFN-γ and IL-17 were reduced, while IL-6 and TNF-α were elevated in the supernatant of splenocytes. At the 4th and 6th weeks of feeding, CPZ caused astrocyte activation and upregulated the expression of BDNF, CNTF, and IGF-II, providing a neurotrophic microenvironment in the brain. At this stage, NG2+ and PDGF-Rα+ oligodendroglia progenitor cells were enhanced in the corpus callosum, but the myelin sheath is still severely lost. Therefore, targeting microglia to improve the inflammatory microenvironment should contribute to the remyelination.
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An Y, Chen Q, Quan N (2011) Interleukin-1 exerts distinct actions on different cell types of the brain in vitro. J Inflamm Res 2011:11–20. https://doi.org/10.2147/JIR.S15357
Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, ing JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4(11):1116–1122. https://doi.org/10.1038/nn738
Barres, Burne, Holtmann et al (1996) Ciliary neurotrophic factor enhances the rate of oligodendrocyte generation. Mol Cell Neurosci 8:146–156. https://doi.org/10.1006/mcne.1996.0053
Bartus K, Burnside ER, Galino J, James ND, Bennett DLH, Bradbury EJ (2019) ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury. Glia 67:1036–1046. https://doi.org/10.1002/glia.23586
Behan PO, Chaudhuri A (2014) EAE is not a useful model for demyelinating disease. Mult Scler Relat Disord 3:565–574. https://doi.org/10.1016/j.msard.2014.06.003
Behrangi N, Namvar N, Ataei M, Dizaji S, Javdani G, Sanati MH (2017) MMP9 gene expression variation by ingesting tart cherry and p-coumaric acid during remyelination in the cuprizone mouse model. Acta Med Iran 55(9):539–549
Brambilla R (2019) The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol 137:757–783. https://doi.org/10.1007/s00401-019-01980-7
Calabretta S, Vogel G, Yu Z et al (2018) Loss of PRMT5 promotes PDGFRalpha degradation during oligodendrocyte differentiation and myelination. Dev Cell 46:426-440.e5. https://doi.org/10.1016/j.devcel.2018.06.025
Fletcher JL, Wood RJ, Nguyen J, Norman EML, Jun CMK, Prawdiuk AR, Biemond M, Nguyen HTH, Northfield SE, Hughes RA, Gonsalvez DG, Xiao J, Murray SS (2018) Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain. J Neurosci 38:7088–7099. https://doi.org/10.1523/JNEUROSCI.0487-18.2018
Franklin RJM, Ffrench-Constant C, Edgar JM, Smith KJ (2012) Neuroprotection and repair in multiple sclerosis. Nat Rev Neurol 8:624–634. https://doi.org/10.1038/nrneurol.2012.200
Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214:1351–1370. https://doi.org/10.1084/jem.20150237
Govier-Cole AE, Wood RJ, Fletcher JL et al (2019) Inhibiting bone morphogenetic protein 4 type i receptor signaling promotes remyelination by potentiating oligodendrocyte differentiation. eNeuro 6:e0399–e0318. https://doi.org/10.1523/ENEURO.0399-18.2019
Gudi V, Gingele S, Skripuletz T, Stangel M (2014) Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned. Front Cell Neurosci 8:73. https://doi.org/10.3389/fncel.2014.00073
Herder V, Hansmann F, Stangel M, Schaudien D, Rohn K, Baumgärtner W, Beineke A (2012) Cuprizone inhibits demyelinating leukomyelitis by reducing immune responses without virus exacerbation in an infectious model of multiple sclerosis. J Neuroimmunol 244(1-2):84–93. https://doi.org/10.1016/j.jneuroim.2012.01.010
Herranz E, Gianni C, Louapre C et al (2016) Neuroinflammatory component of gray matter pathology in multiple sclerosis. Ann Neurol 80:776–790. https://doi.org/10.1002/ana.24791
Kang Z, Liu L, Spangler R et al (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 13;32(24):8284–8292. https://doi.org/10.1523/JNEUROSCI.0841-12.2012
Kim M, Carman CV, Springer TA (2003) Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301:1720–1725. https://doi.org/10.1126/science.1084174
Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118(6):723–736. https://doi.org/10.1007/s00401-009-0591-3
Kipp M, Nyamoya S, Hochstrasser T, Amor S (2017) Multiple sclerosis animal models: a clinical and histopathological perspective. Brain Pathol 27:123–137. https://doi.org/10.1111/bpa.12454
Klegeris A, Giasson BI, Zhang H et al (2006) Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in human astrocytes and astrocytoma cells. FASEB J 20:2000–2008. https://doi.org/10.1096/fj.06-6183com
Komegae EN, Souza TA, Grund LZ, Lima C, Lopes-Ferreira M (2017) Multiple functional therapeutic effects of TnP: A small stable synthetic peptide derived from fish venom in a mouse model of multiple sclerosis. PLoS One 12(2):e0171796. https://doi.org/10.1371/journal.pone.0171796 eCollection 2017
Komoly S, Hudson LD, Webster HD, Bondy CA (1992) Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc Natl Acad Sci U S A 89:1894–1898. https://doi.org/10.1073/pnas.89.5.1894
Kramann N, Menken L, Pfortner R et al (2019) Glial fibrillary acidic protein expression alters astrocytic chemokine release and protects mice from cuprizone-induced demyelination. Glia 67:1308–1319. https://doi.org/10.1002/glia.23605
Labunets IF, Rodnichenko AE (2019) Melatonin effects in young and aged mice with toxic cuprizone-induced model of demyelination. Adv Gerontol 32(3):338–346
Lassmann H, Bradl M (2017) Multiple sclerosis: experimental models and reality. Acta Neuropathol 133:223–244. https://doi.org/10.1007/s00401-016-1631-4
Li W, Suwanwela NC, Patumraj S (2017) Curcumin prevents reperfusion injury following ischemic stroke in rats via inhibition of NFkappaB, ICAM-1, MMP-9 and caspase-3 expression. Mol Med Rep 16:4710–4720. https://doi.org/10.3892/mmr.2017.7205
Lub M, van Kooyk Y, van Vliet SJ, Figdor CG (1997) Dual role of the actin cytoskeleton in regulating cell adhesion mediated by the integrin lymphocyte function-associated molecule-1. Mol Biol Cell 8:341–351. https://doi.org/10.1091/mbc.8.2.341
Lutton EM, Razmpour R, Andrews AM, Cannella LA, Son YJ, Shuvaev VV, Muzykantov VR, Ramirez SH (2017) Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury. Sci Rep 7:3846. https://doi.org/10.1038/s41598-017-03309-4
Madadi S, Pasbakhsh P, Tahmasebi F, Mortezaee K, Khanehzad M, Boroujeni FB, Noorzehi G, Kashani IR (2019) Astrocyte ablation induced by La-aminoadipate (L-AAA) potentiates remyelination in a cuprizone demyelinating mouse model. Metab Brain Dis 34:593–603. https://doi.org/10.1007/s11011-019-0385-9
Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193. https://doi.org/10.1016/S1474-4422(14)70256-X
Mana P, Fordham SA, Staykova MA et al (2009) Demyelination caused by the copper chelator cuprizone halts T cell mediated autoimmune neuroinflammation. J Neuroimmunol 210:13–21. https://doi.org/10.1016/j.jneuroim.2009.02.013
McMahon EJ, Suzuki K, Matsushima GK et al (2002) Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J Neuroimmunol 130(1-2):32–45. https://doi.org/10.1016/s0165-5728(02)00205-9
Miklossy J, Doudet DD, Schwab C et al (2006) Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 197:275–283. https://doi.org/10.1016/j.expneurol.2005.10.034
Nakahara H, Konishi Y, Beach TG, Yamada N, Makino S, Tooyama I (2010) Infiltration of T lymphocytes and expression of icam-1 in the hippocampus of patients with hippocampal sclerosis. Acta Histochem Cytochem 43:157–162. https://doi.org/10.1267/ahc.10022
Nystad AE, Wergeland S, Aksnes L, Myhr KM, Bø L, Torkildsen O (2014) Effect of high-dose 1.25 dihydroxyvitamin D3 on remyelination in the cuprizone model. APMIS 122(12):1178–1186. https://doi.org/10.1111/apm.12281
Patel R, Hossain MA, German N, Al-Ahmad AJ (2018) Gliotoxin penetrates and impairs the integrity of the human blood-brain barrier in vitro. Mycotoxin Res 34:257–268. https://doi.org/10.1007/s12550-018-0320-7
Petkovic F, Campbell IL, Gonzalez B, Castellano B (2017) Reduced cuprizone-induced cerebellar demyelination in mice with astrocyte-targeted production of IL-6 is associated with chronically activated, but less responsive microglia. J Neuroimmunol 310:97–102. https://doi.org/10.1016/j.jneuroim.2017.07.003
Pfeifenbring S, Bunyan RF, Metz I, Röver C, Huppke P, Gärtner J, Lucchinetti CF, Brück W (2015) Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol 77:655–667. https://doi.org/10.1002/ana.24364
Pirko I, Johnson AJ (2008) Neuroimaging of demyelination and remyelination models. Curr Top Microbiol Immunol 318:241–266
Praet J, Guglielmetti C, Berneman Z, van der Linden A, Ponsaerts P (2014) Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 47:485–505. https://doi.org/10.1016/j.neubiorev.2014.10.004
Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170(5):1713–1724. https://doi.org/10.2353/ajpath.2007.060783
Scott GS, Kean RB, Fabis MJ et al (2004) ICAM-1 upregulation in the spinal cords of PLSJL mice with experimental allergic encephalomyelitis is dependent upon TNF-alpha production triggered by the loss of blood-brain barrier integrity. J Neuroimmunol 155:32–42. https://doi.org/10.1016/j.jneuroim.2004.05.011
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. https://doi.org/10.1093/brain/aws262
Sui R-X, Miao Q, Wang J et al (2019) Protective and therapeutic role of Bilobalide in cuprizone-induced demyelination. Int Immunopharmacol 66:69–81. https://doi.org/10.1016/j.intimp.2018.09.041
Vega-Riquer JM, Mendez-Victoriano G, Morales-Luckie RA, Gonzalez-Perez O (2019) Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases. Curr Neuropharmacol 17:129–141. https://doi.org/10.2174/1570159X15666170717120343
Weller RO (1998) Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 57(10):885–894. https://doi.org/10.1097/00005072-199810000-00001
Wu T, Zhang A, Lu H, Cheng Q (2018) The Role and Mechanism of Borneol to Open the Blood-Brain Barrier. Integr Cancer Ther 17:806–812. https://doi.org/10.1177/1534735418767553
Yang J, Fei M, Gu Y et al (2008) Evaled expression of ICAM-1 and its ligands in the rat spinal cord following lipopolysaccharide intraspinal injection. Neuromolecular Med 10(4):385–392. https://doi.org/10.1007/s12017-008-8049-7
Zhao C, Ma D, Zawadzka M, Fancy SP, Elis-Williams L, Bouvier G, Stockley JH, de Castro GM, Wang B, Jacobs S, Casaccia P, Franklin RJ (2015) Sox2 sustains recruitment of oligodendrocyte progenitor cells following CNS demyelination and primes them for differentiation during remyelination. J Neurosci 35:11482–11499. https://doi.org/10.1523/JNEUROSCI.3655-14.2015
Zheng P, Fu H, Wei G, Wei Z, Zhang J, Ma X, Rui D, Meng X, Ming L (2016) Antigen-oriented T cell migration contributes to myelin peptide induced-EAE and immune tolerance. Clin Immunol 169:36–46. https://doi.org/10.1016/j.clim.2016.06.004
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This work was supported by grants from the National Natural Science Foundation of China (No. 81371414 and 81473577), and Research Project Supported by Shanxi Scholarship Council of China (2014-7).
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An, J., Yin, JJ., He, Y. et al. Temporal and Spatial Dynamics of Astroglial Reaction and Immune Response in Cuprizone-Induced Demyelination. Neurotox Res 37, 587–601 (2020). https://doi.org/10.1007/s12640-019-00129-4
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DOI: https://doi.org/10.1007/s12640-019-00129-4