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Journal of Neuroinflammation

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Open Access 01-12-2016 | Research

Cuprizone demyelination induces a unique inflammatory response in the subventricular zone

Authors: James M. Hillis, Julie Davies, Mayara Vieira Mundim, Osama Al-Dalahmah, Francis G. Szele

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Cuprizone leads to demyelination of the corpus callosum (CC) and activates progenitor cells in the adjacent subventricular zone (SVZ), a stem cell niche which contributes to remyelination. The healthy SVZ contains semi-activated microglia and constitutively expresses the pro-inflammatory molecule galectin-3 (Gal-3) suggesting the niche uniquely regulates inflammation.

Methods

We studied the inflammatory response to cuprizone in the SVZ and CC in Gal-3 knockout mice using immunohistochemistry and with the in vitro neurosphere assay.

Results

Cuprizone caused loss of myelin basic protein (MBP) immunofluorescence in the CC suggesting demyelination. Cuprizone increased the density of CD45+/Iba1+ microglial cells and also increased Gal-3 expression in the CC. Surprisingly, the number of Gal-3+ and CD45+ cells decreased in the SVZ after cuprizone, suggesting inflammation was selectively reduced therein. Inflammation can regulate SVZ proliferation and indeed the number of phosphohistone H3+ (PHi3+) cells decreased in the SVZ but increased in the CC in both genotypes after cuprizone treatment. BrdU+ SVZ cell numbers also decreased in the SVZ after cuprizone, and this effect was significantly greater at 3 weeks in Gal-3 ^−/− mice compared to WT, suggesting Gal-3 normally limits SVZ cell emigration following cuprizone treatment.

Conclusions

This study reveals a uniquely regulated inflammatory response in the SVZ and shows that Gal-3 participates in remyelination in the cuprizone model. This contrasts with more severe models of demyelination which induce SVZ inflammation and suggests the extent of demyelination affects the SVZ neurogenic response.

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Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–17.CrossRefPubMed

Mechelli R, Annibali V, Ristori G, Vittori D, Coarelli G, Salvetti M. Multiple sclerosis etiology: beyond genes and environment. Expert Rev Clin Immunol. 2010;6:481–90.CrossRefPubMed

Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. The relevance of animal models in multiple sclerosis research. Pathophysiology. 2011;18:21–9.CrossRefPubMed

Bakker DA, Ludwin SK. Blood-brain barrier permeability during cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases. J Neurol Sci. 1987;78:125–37.CrossRefPubMed

Kondo A, Nakano T, Suzuki K. Blood-brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice. Brain Res. 1987;425:186–90.CrossRefPubMed

McMahon EJ, Suzuki K, Matsushima GK. Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J Neuroimmunol. 2002;130:32–45.CrossRefPubMed

Torkildsen O, Brunborg LA, Myhr KM, Bo L. The cuprizone model for demyelination. Acta Neurol Scand Suppl. 2008;188:72–6.CrossRefPubMed

Zendedel A, Beyer C, Kipp M. Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. J Mol Neurosci. 2013.

Ihrie RA, Alvarez-Buylla A. Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. Neuron. 2011;70:674–86.CrossRefPubMedPubMedCentral

10.

Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, Ng SW, Kilpatrick TJ, Merson TD. Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci. 2014;34:14128–46.CrossRefPubMed

11.

Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A. Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci. 2006;26:7907–18.CrossRefPubMed

12.

Goings GE, Sahni V, Szele FG. Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury. Brain Res. 2004;996:213–26.CrossRefPubMed

13.

Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R, Baron-Van Evercooren A. Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci U S A. 2007;104:4694–9.CrossRefPubMedPubMedCentral

14.

Dawson JD. The histology of disseminated sclerosis. Royal Soc Edin. 1916;50:517–740.CrossRef

15.

Goings GE, Kozlowski DA, Szele FG. Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain. Glia. 2006;54:329–42.CrossRefPubMed

16.

James RE, Hillis J, Adorjan I, Gration B, Mundim MV, Iqbal AJ, Majumdar MM, Yates RL, Richards MM, Goings GE, et al. Loss of galectin-3 decreases the number of immune cells in the subventricular zone and restores proliferation in a viral model of multiple sclerosis. Glia. 2016;64:105–21.CrossRefPubMed

17.

Goings GE, Greisman A, James RE, Abram LK, Begolka WS, Miller SD, Szele FG. Hematopoietic cell activation in the subventricular zone after Theiler’s virus infection. J Neuroinflammation. 2008;5:44–66.CrossRefPubMedPubMedCentral

18.

Ekdahl CT, Claasen J-H, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632–7.CrossRefPubMedPubMedCentral

19.

Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–5.CrossRefPubMed

20.

Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall 2nd GP, Scheffler B, Steindler DA. Microglia instruct subventricular zone neurogenesis. Glia. 2006;54:815–25.CrossRefPubMed

21.

Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci. 2014;34:2231–43.CrossRefPubMedPubMedCentral

22.

Comte I, Kim Y, Young CC, van der Harg JM, Hockberger P, Bolam PJ, Poirier F, Szele FG. Galectin-3 maintains cell motility from the subventricular zone to the olfactory bulb. J Cell Sci. 2011;124:2438–47.CrossRefPubMedPubMedCentral

23.

Stancic M, van Horssen J, Thijssen VL, Gabius HJ, van der Valk P, Hoekstra D, Baron W. Increased expression of distinct galectins in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2011;37:654–71.CrossRefPubMed

24.

Ho MK, Springer TA. Mac-2, a novel 32,000 Mr mouse macrophage subpopulation-specific antigen defined by monoclonal antibodies. J Immunol. 1982;128:1221–8.PubMed

25.

Jiang HR, Al Rasebi Z, Mensah-Brown E, Shahin A, Xu D, Goodyear CS, Fukada SY, Liu FT, Liew FY, Lukic ML. Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J Immunol. 2009;182:1167–73.CrossRefPubMed

26.

Pasquini LA, Millet V, Hoyos HC, Giannoni JP, Croci DO, Marder M, Liu FT, Rabinovich GA, Pasquini JM. Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function. Cell Death Differ. 2011.

27.

Hoyos HC, Rinaldi M, Mendez-Huergo SP, Marder M, Rabinovich GA, Pasquini JM, Pasquini LA. Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination. Neurobiol Dis. 2014;62:441–55.CrossRefPubMed

28.

Mason JL, Ye P, Suzuki K, D'Ercole AJ, Matsushima GK. Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. J Neurosci. 2000;20:5703–8.PubMed

29.

Kim Y, Wang WZ, Comte I, Pastrana E, Tran PB, Brown J, Miller RJ, Doetsch F, Molnar Z, Szele FG. Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J Neurochem. 2010;114:750–60.CrossRefPubMedPubMedCentral

30.

Kornguth SE, Anderson JW. Localization of a basic protein in the myelin of various species with the aid of fluorescence and electron microscopy. J Cell Biol. 1965;26:157–66.CrossRefPubMedPubMedCentral

31.

Laatsch RH, Kies MW, Gordon S, Alvord Jr EC. The encephalomyelitic activity of myelin isolated by ultracentrifugation. J Exp Med. 1962;115:777–88.CrossRefPubMedPubMedCentral

32.

Young CC, Al-Dalahmah O, Lewis NJ, Brooks KJ, Jenkins MM, Poirier F, Buchan AM, Szele FG. Blocked angiogenesis in Galectin-3 null mice does not alter cellular and behavioral recovery after middle cerebral artery occlusion stroke. Neurobiol Dis. 2014;63:155–64.CrossRefPubMed

33.

Taylor LC, Gilmore W, Ting JP, Matsushima GK. Cuprizone induces similar demyelination in male and female C57BL/6 mice and results in disruption of the estrous cycle. J Neurosci Res. 2010;88:391–402.CrossRefPubMed

34.

Song SK, Yoshino J, Le TQ, Lin SJ, Sun SW, Cross AH, Armstrong RC. Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage. 2005;26:132–40.CrossRefPubMed

35.

Bhat RV, Axt KJ, Fosnaugh JS, Smith KJ, Johnson KA, Hill DE, Kinzler KW, Baraban JM. Expression of the APC tumor suppressor protein in oligodendroglia. Glia. 1996;17:169–74.CrossRefPubMed

36.

Kim EJ, Leung CT, Reed RR, Johnson JE. In vivo analysis of Ascl1 defined progenitors reveals distinct developmental dynamics during adult neurogenesis and gliogenesis. J Neurosci. 2007;27:12764–74.CrossRefPubMed

37.

Sakaguchi M, Shingo T, Shimazaki T, Okano HJ, Shiwa M, Ishibashi S, Oguro H, Ninomiya M, Kadoya T, Horie H, et al. A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells. Proc Natl Acad Sci U S A. 2006;103:7112–7.CrossRefPubMedPubMedCentral

38.

Dizon MLV, Szele FG. The subventricular zone responds dynamically to mechanical brain injuries. In: Levison SW, editor. Mammalian subventricular zones: their roles in brain development, cell replacement, and disease. New York: Kluwer Academic/Plenum Publishers; 2005. p. 210–41.

39.

Shibata K, Ajiro K. Cell cycle-dependent suppressive effect of histone H1 on mitosis-specific H3 phosphorylation. J Biol Chem. 1993;268:18431–4.PubMed

40.

Mason JL, Suzuki K, Chaplin DD, Matsushima GK. Interleukin-1beta promotes repair of the CNS. J Neurosci. 2001;21:7046–52.PubMed

41.

Sirko S, Irmler M, Gascon S, Bek S, Schneider S, Dimou L, Obermann J, De Souza Paiva D, Poirier F, Beckers J, et al. Astrocyte reactivity after brain injury-: the role of galectins 1 and 3. Glia. 2015.

42.

Young CC, Brooks KJ, Buchan AM, Szele FG. Cellular and molecular determinants of stroke-induced changes in subventricular zone cell migration. Antioxid Redox Signal. 2011;14:1877–88.CrossRefPubMedPubMedCentral

43.

Thomas LB, Gates MA, Steindler DA. Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway. Glia. 1996;17:1–14.CrossRefPubMed

44.

Mercier F, Kitasako JT, Hatton GI. Anatomy of the brain neurogenic zones revisited: fractones and the fibroblast/macrophage network. J Comp Neurol. 2002;451:170–88.CrossRefPubMed

45.

Kokaia Z, Martino G, Schwartz M, Lindvall O. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci. 2012;15:1078–87.CrossRefPubMed

46.

Szele FG, Chesselet MF. Cortical lesions induce an increase in cell number and PSA-NCAM expression in the subventricular zone of adult rats. J Comp Neurol. 1996;368:439–54.CrossRefPubMed

47.

Young CC, van der Harg JM, Lewis NJ, Brooks KJ, Buchan AM, Szele FG. Ependymal ciliary dysfunction and reactive astrocytosis in a reorganized subventricular zone after stroke. Cereb Cortex. 2013;23:647–59.CrossRefPubMed

48.

Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature. 2003;422:688–94.CrossRefPubMed

49.

Jin K, Wang X, Xie L, Mao XO, Greenberg DA. Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice. Proc Natl Acad Sci U S A. 2010;107:7993–8.CrossRefPubMedPubMedCentral

50.

DeLuca GC, Joseph A, George J, Yates RL, Hamard M, Hofer M, Esiri MM. Olfactory pathology in central nervous system demyelinating diseases. Brain Pathol. 2015;25:543–51.CrossRefPubMed

51.

Nait-Oumesmar B, Decker L, Lachapelle F, Avellana-Adalid V, Bachelin C, Van Evercooren AB. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur J Neurosci. 1999;11:4357–66.CrossRefPubMed

52.

Jablonska B, Aguirre A, Raymond M, Szabo G, Kitabatake Y, Sailor KA, Ming GL, Song H, Gallo V. Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci. 2010;13:541–50.CrossRefPubMedPubMedCentral

53.

Colnot C, Fowlis D, Ripoche MA, Bouchaert I, Poirier F. Embryonic implantation in galectin 1/galectin 3 double mutant mice. Dev Dyn. 1998;211:306–13.CrossRefPubMed

Title: Cuprizone demyelination induces a unique inflammatory response in the subventricular zone
Authors: James M. Hillis
Julie Davies
Mayara Vieira Mundim
Osama Al-Dalahmah
Francis G. Szele
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0651-2

ACC 2024 Congress

Springer Medicine

Cuprizone demyelination induces a unique inflammatory response in the subventricular zone

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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