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

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.

IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation

“…1). The differential expression of Il4i1 during remyelination is in opposition to the expression pattern of genes associated with proinflammatory activity, such as Mmp12 (Vos et al , 2003; Hansmann et al , 2012). This result indicates that Il4i1 is upregulated during inflammation resolution and at the onset of oligodendrocyte differentiation, suggesting that IL4I1 may be involved in modulating inflammation or promoting remyelination.…”

Crosstalk between cerebral endothelium and oligodendrocyte

“…Moreover, after white matter injury, MMP-9 removed injury-induced deposition of inhibitory NG2 proteoglycan, which is an essential step for OPCs to differentiate into mature oligodendrocytes for remyelination 131 . In addition, MMP-12 was shown to cause demyelination, macrophage infiltration, and motor deficits in a mouse model of virus-induced multiple sclerosis 132 . Tissue inhibitor of metalloproteinases might be also involved in cellular function/survival of oligodendrocyte linage cells.…”

Enhanced expression of matrix metalloproteinase-12 contributes to Npc1 deficiency-induced axonal degeneration

“…A recent study showed that MMP-12 knockout in mice reduced Theiler’s murine encephalomyelitis (TME)-induced demyelination, macrophage infiltration, and motor deficits (Hansmann et al , 2012), further supporting the role of MMP-12 in MS. However, the exact mechanism underlying MMP-12-induced demyelination and axonal degeneration is not clear.…”