The Role of Galectin-3: From Oligodendroglial Differentiation and Myelination to Demyelination and Remyelination Processes in a Cuprizone-Induced Demyelination Model

  • H. C. Hoyos
  • Mariel Marder
  • R. Ulrich
  • V. Gudi
  • M. Stangel
  • G. A. Rabinovich
  • L. A. Pasquini
  • J. M. Pasquini
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 949)

Abstract

The aim of this work was to combine our previously published results with our new data to show how galectin-3 (Gal-3) controls myelin integrity and function, promotes oligodendroglial cell differentiation, and regulates microglial responses to limit cuprizone- (CPZ)-induced demyelination and foster remyelination. In this study, 8-week-old Gal-3-deficient (Lgals3 /) and wild type (WT) mice were fed a diet containing 0.2 % CPZ w/w for 6 weeks, after which CPZ was withdrawn in order to allow remyelination. Our results show that remyelination was less efficient in Lgals3 / than in WT mice. Electron microscopic images from remyelinated sections in Lgals3 / mice revealed collapsed axons with a defective myelin wrap, while remyelinated WT mice had normal axons without relevant myelin wrap disruption. MMP-3 expression increased during remyelination in WT but not in Lgals3 / mice. The number of CD45+, TNFα+ and TREM-2b+ cells decreased only in WT mice only, with no alterations in Lgals3 −/− mice during demyelination and remyelination. Therefore, Gal-3 influences remyelination by mechanisms involving the tuning of microglial cells, modulation of MMP activity, and changes in myelin architecture.

Keywords

Galectin-3 Myelination Demyelination Remyelination Cuprizone Microglia Oligodendrocytes MMPs 

Abbreviations

MMPs

Matrix metalloproteinases

Gal-3

Galectin-3

Lgals3/

Gal-3-deficient

WT

Wild type

CPZ

Cuprizone

CRD

Carbohydrate-recognition domain

CNS

Central nervous system

OLG

Oligodendrocyte

EAE

Experimental Autoimmune Encephalomyelitis

CC

Corpus callosum

OPC

Oligodendrocyte precursor cells

MBP

Myelin basic protein

PBS

Phosphate buffered saline

PFA

Paraformaldehyde

SVZ

Subventricular zone

EM

Electron Microscopy

GFAP

Glial Fibrillary Acidic Protein

IOD

Integrated optical density

References

  1. Chandler S, Coates R, Gearing A, Lury J, Wells G, Bone E (1995) Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett 201:223–226CrossRefPubMedGoogle Scholar
  2. Chandler S, Cossins J, Lury J, Wells G (1996) Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun 228:421–429CrossRefPubMedGoogle Scholar
  3. Chernoff GF (1981) Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J Hered 72:128PubMedGoogle Scholar
  4. David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:388–399CrossRefPubMedGoogle Scholar
  5. Franco-Pons N, Torrente M, Colomina MT, Vilella E (2007) Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett 169:205–213CrossRefPubMedGoogle Scholar
  6. Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 11:839–855CrossRefGoogle Scholar
  7. Franklin RJ, Kotter MR (2008) The biology of CNS remyelination: the key to therapeutic advances. J Neurol 255:19–25CrossRefPubMedGoogle Scholar
  8. Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394CrossRefPubMedGoogle Scholar
  9. Hansmann F, Herder V, Kalkuhl A, Haist V, Zhang N, Schaudien D, Deschl U, Baumgärtner W, Ulrich R (2012) Matrix metalloproteinase-12 deficiency ameliorates clinical course and demyelination in Theiler’s murine encephalomyelitis. Acta Neuropathol 124:127–142CrossRefPubMedGoogle Scholar
  10. Hoyos HC, Rinaldi M, Mendez-Huergo SP, Marder M, Rabinovich GA, Pasquini JM, Pasquini LA (2014) Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination. Neurobiol Dis 62:441–455CrossRefPubMedGoogle Scholar
  11. Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, Liu FT (2000) Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol 156:1073–1083CrossRefPubMedPubMedCentralGoogle Scholar
  12. Jiang HR, Al Rasebi Z, Mensah-Brown E, Shahin A, Xu D, Goodyear CS, Fukada SY, Liu FT, Liew FY, Lukic ML (2009) Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J. Immunol 182:1167–1173CrossRefPubMedGoogle Scholar
  13. Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347CrossRefPubMedGoogle Scholar
  14. Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118:723–736CrossRefPubMedGoogle Scholar
  15. Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332CrossRefPubMedGoogle Scholar
  16. Lalancette-Hébert M, Swarup V, Beaulieu JM, Bohacek I, Abdelhamid E, Weng YC, Sato S, Kriz J (2012) Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. J Neurosci 32:10383–10395CrossRefPubMedGoogle Scholar
  17. Li Y, Komai-Koma M, Gilchrist DS, Hsu DK, Liu FT, Springall T, Xu D (2008) Galectin-3 is a negative regulator of lipopolysaccharide-mediated inflammation. J Immunol 181:2781–2789CrossRefPubMedGoogle Scholar
  18. Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27:50–58CrossRefPubMedGoogle Scholar
  19. Masuda-Nakagawa LM, Muller KJ, Nicholls JG (1993) Axonal sprouting and laminin appearance after destruction of glial sheaths. Proc Natl Acad Sci USA 90(11):4966–4970CrossRefPubMedPubMedCentralGoogle Scholar
  20. Matsushima GK, Morell P (2001) The neurotoxicant cuprizone as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116CrossRefPubMedGoogle Scholar
  21. McMahon EJ, Suzuki K, Matsushima GK (2002) Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood–brain barrier. J Neuroimmunol 130:32–45CrossRefPubMedGoogle Scholar
  22. Mok SW, Thelen KM, Riemer C, Bamme T, Gültner S, Lütjohann D, Baier M (2006) Simvastatin prolongs survival times in prion infections of the central nervous system. Biochem Biophys Res Commun 348:697–702CrossRefPubMedGoogle Scholar
  23. Mok SW, Riemer C, Madela K, Hsu DK, Liu FT, Gültner S, Heise I, Baier M (2007) Role of galectin-3 in prion infections of the CNS. Biochem Biophys Res Commun 359:672–678CrossRefPubMedGoogle Scholar
  24. Ochieng J, Fridman R, Nangia-Makker P, Kleiner DE, Liotta LA, Stetler-Stevenson WG, Raz A (1994) Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and -9. Biochemistry 33:14109–14114CrossRefPubMedGoogle Scholar
  25. Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, Boddeke HW (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60:306–321CrossRefPubMedGoogle Scholar
  26. Pasquini LA, Millet V, Hoyos HC, Giannoni JP, Croci DO, Marder M, Liu FT, Rabinovich GA, Pasquini JM (2011) Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function. Cell Death Differ 18:1746–1756CrossRefPubMedPubMedCentralGoogle Scholar
  27. Rabinovich GA, Croci DO (2012) Regulatory circuits mediated by lectin–glycan interactions in autoimmunity and cancer. Immunity 36:322–335CrossRefPubMedGoogle Scholar
  28. Rabinovich GA, Toscano MA (2009) Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9:338–352CrossRefPubMedGoogle Scholar
  29. Rabinovich GA, Toscano MA, Jackson SS, Vasta GR (2007) Functions of cell surface galectin glycoprotein lattices. Curr Opin Struct Biol 17:513–520CrossRefPubMedPubMedCentralGoogle Scholar
  30. Ransohoff RM, Brown MA (2012) Innate immunity in the Central Nervous System. J Clin Invest 122:1164–1171CrossRefPubMedPubMedCentralGoogle Scholar
  31. Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170:1713–1724CrossRefPubMedPubMedCentralGoogle Scholar
  32. Riemer C, Neidhold S, Burwinkel M, Schwarz A, Schultz J, Krätzschmar J, Mönning U, Baier M (2004) Gene expression profiling of scrapie-infected brain tissue. Biochem Biophys Res Commun 323:556–564CrossRefPubMedGoogle Scholar
  33. Shiryaev SA, Savinov AY, Cieplak P, Ratnikov BI, Motamedchaboki K, Smith JW, Strongin AY (2009) Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. PLoS One 4(3):e4952CrossRefPubMedPubMedCentralGoogle Scholar
  34. Skuljec J, Gudi V, Ulrich R, Frichert K, Yildiz O, Pul R, Voss EV, Wissel K, Baumgärtner W, Stangel M (2011) Matrix metalloproteinases and their tissue inhibitors in cuprizone-induced demyelination and remyelination of brain white and gray matter. J Neuropathol Exp Neurol 70:758–769CrossRefPubMedGoogle Scholar
  35. Smith GS, Sambroska B, Hawley SP, Klaiman JM, Gillis TE, Jones N, Boggs JM, Harauz G (2013) Nucleus-localized 21.5-kDa myelin basic protein promotes oligodendrocyte proliferation and enhances neurite outgrowth in coculture, unlike the plasma membrane-associated 18.5-kDa isoform. J Neurosci Res 91:349–362CrossRefPubMedGoogle Scholar
  36. Stadelmann C (2011) Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr Opin Neurol 24:224–229CrossRefPubMedGoogle Scholar
  37. Stancic M, Slijepcevic D, Nomden A, Vos MJ, de Jonge JC, Sikkema AH, Gabius HJ, Hoekstra D, Baron W (2012) Galectin-4, a novel neuronal regulator of myelination. Glia 60:919–935CrossRefPubMedGoogle Scholar
  38. Ulrich R, Gerhauser I, Seeliger F, Baumgärtner W, Alldinger S (2005) Matrix metalloproteinases and their inhibitors in the developing mouse brain and spinal cord: A reverse transcription quantitative polymerase chain reaction study. Dev Neurosci 27:408–418CrossRefPubMedGoogle Scholar
  39. Ulrich R, Baumgärtner W, Gerhauser I, Seeliger F, Haist V, Deschl U, Alldinger S (2006) MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating Theiler murine encephalomyelitis. J Neuropathol Exp Neurol 65:783–793CrossRefPubMedGoogle Scholar
  40. Ulrich R, Seeliger F, Kreutzer M, Germann PG, Baumgärtner W (2008) Limited remyelination in Theiler’s murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells. Neuropathol Appl Neurobiol 34:603–620CrossRefPubMedGoogle Scholar
  41. von Bernhardi R, Muller KJ (1995) Repair of the central nervous system: lessons from lesions in leeches. J Neurobiol 27(3):353–366CrossRefGoogle Scholar
  42. Voss EV, Škuljec J, Gudi V, Skripuletz T, Pul R, Trebst C, Stangel M (2012) Characterisation of microglia during de- and remyelination: can they create a repair promoting environment? Neurobiol Dis 45:519–528Google Scholar
  43. Williams A, Piaton G, Lubetzki C (2007) Astrocytes-friends or foes in multiple sclerosis? Glia 55:1300–1312Google Scholar
  44. Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM (2009) Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci 123:418–429CrossRefPubMedGoogle Scholar
  45. Yang RY, Rabinovich GA, Liu FT (2008) Galectins: structure, function and therapeutic potential. Expert Rev Mol Med 10:e17CrossRefPubMedGoogle Scholar
  46. Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 7:502–511CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • H. C. Hoyos
    • 1
    • 2
  • Mariel Marder
    • 1
    • 2
  • R. Ulrich
    • 3
  • V. Gudi
    • 4
    • 5
  • M. Stangel
    • 4
    • 5
  • G. A. Rabinovich
    • 6
    • 7
  • L. A. Pasquini
    • 1
    • 2
    • 8
  • J. M. Pasquini
    • 1
    • 2
    • 8
  1. 1.Department of Biological Chemistry, School of Pharmacy and BiochemistryInstitute of Chemistry and Biological Physical Chemistry (IQUIFIB)Buenos AiresArgentina
  2. 2.School of Pharmacy and BiochemistryUniversity of Buenos Aires and National Research Council (CONICET)Buenos AiresArgentina
  3. 3.Department of PathologyUniversity of Veterinary Medicine HannoverHannoverGermany
  4. 4.Department of NeurologyHannover Medical SchoolHannoverGermany
  5. 5.Center for System NeurosciencesHannoverGermany
  6. 6.Laboratory of ImmunopathologyInstitute of Biology and Experimental Medicine (IBYME; CONICET)Buenos AiresArgentina
  7. 7.Laboratory of Functional Glycomics, Department of Biological Chemistry, Faculty of Exact and Natural SciencesUniversity of Buenos AiresBuenos AiresArgentina
  8. 8.Dpto. de Qca BiolFFyB-UBABs asArgentina

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