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Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis

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Abstract

Matrix metalloproteinases (MMPs) are a family of extracellular proteases involved in the pathogenesis of demyelinating diseases like multiple sclerosis (MS). The aim of the present study was to investigate whether MMPs induce direct myelin degradation, leukocyte infiltration, disruption of the blood–brain barrier (BBB), and/or extracellular matrix remodeling in the pathogenesis of Theiler’s murine encephalomyelitis (TME), a virus-induced model of MS. During the demyelinating phase of TME, the highest transcriptional upregulation was detected for Mmp12, followed by Mmp3. Mmp12 −/− mice showed reduced demyelination, macrophage infiltration, and motor deficits compared with wild-type- and Mmp3 knock-out mice. However, BBB remained unaltered, and the amount of extracellular matrix deposition was similar in knock-out mice and wild-type mice. Furthermore, stereotaxic injection of activated MMP-3, -9, and -12 into the caudal cerebellar peduncle of adult mice induced a focally extensive primary demyelination prior to infiltration of inflammatory cells, as well as a reduction in the number of oligodendrocytes and a leakage of BBB. All these results demonstrate that MMP-12 plays an essential role in the pathogenesis of TME, most likely due to its primary myelin- or oligodendrocyte-toxic potential and its role in macrophage extravasation, whereas there was no sign of BBB damage or alterations to extracellular matrix remodeling/deposition. Thus, interrupting the MMP-12 cascade may be a relevant therapeutic approach for preventing chronic progressive demyelination.

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Acknowledgments

The authors thank Bettina Buck, Thomas Feidl, Martin Gamber, Petra Grünig, Michael Müller, Kerstin Rohn, Caroline Schütz, Anuschka Unold, and Heinz Theobald for excellent technical assistance. Furthermore, we are grateful to Dr. Karl Rohn, Department of Biometry, Epidemiology and Information Processing, University of Veterinary Medicine Hannover, Germany, for statistical assistance; Prof. Christiane Pfarrer, Department of Anatomy, University of Veterinary Medicine Hannover, Germany for providing the fluorescence microscope; Dr. Maren Luchtefeld, Department of Cardiology and Angiology, Hannover Medical School, Germany for providing the fluorescence reader; Prof. Klaus Schughart, Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany for help with planning the cross-breeding of the Mmp knockout animals; and Frances Sherwood-Brock for her helpful comments on the manuscript. The BeAn strain of TMEV was a generous gift of Dr. Howard L. Lipton, Department of Microbiology–Immunology, University of Illinois, Chicago, USA. Florian Hansmann and Vanessa Herder were supported by scholarships from the National Academic Research Foundation (Germany) or the Ministry of Lower Saxony (Germany), respectively. Reiner Ulrich received a grant from the Centre for Systems Neuroscience Hannover (Germany). The authors have no conflicting financial interests.

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Authors and Affiliations

  1. Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany

    Florian Hansmann, Vanessa Herder, Verena Haist, Ning Zhang, Dirk Schaudien, Wolfgang Baumgärtner & Reiner Ulrich

  2. Center for Systems Neuroscience Hannover, Hannover, Germany

    Florian Hansmann, Vanessa Herder, Ning Zhang & Wolfgang Baumgärtner

  3. Department of Non-Clinical Drug Safety, Boehringer Ingelheim Pharma GmbH&Co KG, Biberach (Riß), Germany

    Arno Kalkuhl & Ulrich Deschl

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  1. Florian Hansmann
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Correspondence to Wolfgang Baumgärtner.

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Supplementary Table 1 includes the primer sequences and reaction conditions used for qPCR. Supplementary Table 2 and Supplementary Fig. 1 show the transcriptional changes related to the canonical Metacore™ cell adhesion and extracellular matrix-remodeling pathway. The canonical cell adhesion and ECM remodeling map was taken from the Metacore™ database (GeneGo, St. Joseph, MO, USA). Supplementary Table 3 shows probe sets, official gene symbols, and fold changes along with the respective p-values of all Mmps and Timps included in the Affymetrix mouse genome 430 2.0 array. Supplementary Table 4 displays a comparison of the fold changes detected by gene-expression microarray and RT-qPCR, respectively.

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Hansmann, F., Herder, V., Kalkuhl, A. et al. Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler’s murine encephalomyelitis. Acta Neuropathol 124, 127–142 (2012). https://doi.org/10.1007/s00401-012-0942-3

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