Related Experiment Video
Updated: May 25, 2026
Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues
Published on: May 8, 2016
Matrix metalloproteinase-12 deficiency ameliorates the clinical course and demyelination in Theiler's murine
Florian Hansmann1, Vanessa Herder, Arno Kalkuhl
1Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559, Hannover, Germany.
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.
Insights
Matrix metalloproteinases (MMPs) are key in demyelinating diseases. MMP-12 deficiency reduced demyelination and motor deficits in a mouse model of multiple sclerosis (MS), suggesting it
Area of Science:
- Neuroimmunology
- Molecular Biology
- Pathology
Background:
- Matrix metalloproteinases (MMPs) are implicated in demyelinating diseases like multiple sclerosis (MS).
- Theiler's murine encephalomyelitis (TME) is a viral-induced mouse model of MS, useful for studying disease pathogenesis.
Purpose of the Study:
- To investigate the role of MMPs in myelin degradation, leukocyte infiltration, blood-brain barrier (BBB) disruption, and extracellular matrix remodeling in TME.
- To determine the specific contribution of MMP-12 and MMP-3 in TME pathogenesis.
Main Methods:
- Transcriptional analysis of MMPs during the demyelinating phase of TME.
- Phenotypic analysis of Mmp12 (-/-) and Mmp3 (-/-) mice compared to wild-type.
- Stereotaxic injection of activated MMPs into the mouse brain to assess direct effects.
Main Results:
- Mmp12 showed the highest upregulation during TME demyelination.
- Mmp12 (-/-) mice exhibited reduced demyelination, macrophage infiltration, and motor deficits.
- Direct injection of MMP-3, -9, and -12 induced primary demyelination, oligodendrocyte loss, and BBB leakage.
Conclusions:
- MMP-12 plays a critical role in TME pathogenesis, likely through direct myelin/oligodendrocyte toxicity and promoting macrophage infiltration.
- MMP-12, not BBB integrity or extracellular matrix remodeling, is the primary driver of demyelination in this model.
- Targeting the MMP-12 pathway presents a potential therapeutic strategy for progressive demyelination in MS.
