Abstract
BackgroundMetalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are also involved, including matrilysin/MMP-7 – an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression.ResultsHere we report that MMP-7-deficient (mmp7-/-) mice on the C57Bl/6 background are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG). Brain sections from MOG-primed mmp7-/-mice did not show signs of immune cell infiltration of the CNS, but MOG-primed wild-type mice showed extensive vascular cuffing and mononuclear cell infiltration 15 days after vaccination. At the peak of EAE wild-type mice had MMP-7 immuno-reactive cells in vascular cuffs that also expressed the macrophage markers Iba-1 and Gr-1, as well as tomato lectin. MOG-specific proliferation of splenocytes, lymphocytes, CD4+ and CD8+ cells were reduced in cells isolated from MOG-primed mmp7-/- mice, compared with MOG-primed wild-type mice. However, the adoptive transfer of splenocytes and lymphocytes from MOG-primed mmp7-/- mice induced EAE in naïve wild-type recipients, but not naïve mmp7-/- recipients. Finally, we found that recombinant MMP-7 increased permeability between endothelial cells in an in vitro blood-brain barrier model.ConclusionOur findings suggest that MMP-7 may facilitate immune cell access or re-stimulation in perivascular areas, which are critical events in EAE and multiple sclerosis, and provide a new therapeutic target to treat this disorder.
Highlights
Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS)
Reactive astrocytes produce a variety of factors in response to injury and infection, so we examined whether astrocytes expressed Matrix metalloproteinases (MMPs)-7 during EAE by co-immunostaining for glial fibrillary acidic protein (GFAP)
The proliferation of T cells can only be inferred from 3Hthymidine incorporation studies, so we investigated myelin oligodendrocyte glycoprotein (MOG)-specific responses of CD4+ and CD8+ T cells using carboxy-fluorescein diacetate succinimidyl ester (CFSE) pre-labelling and FACS analysis
Summary
Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are involved, including matrilysin/MMP-7 – an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression. Multiple sclerosis (MS) is an autoimmune disorder marked by the infiltration of pathogenic T cells into the central nervous system (CNS) that cause inflammation and oligodendrocyte cell death. In an animal model of MS, called experimental autoimmune encephalomyelitis (EAE), vaccination with CNS-myelin-derived peptides triggers the expansion of oligodendrocyte-specific T cells and a pathological profile that includes CNS inflammation, demyelination, and paralysis. Transmigration of pathogenic T cells across the blood-brain barrier (BBB) is facilitated by the expression of cell adhesion molecules and proteinases that degrade the ECM [1]. In a delayed-type hypersensitivity model for MS, MMP-7 was found to be the most up-regulated MMP, compared with MMP-2,3,8,9,10,11,12,13,14,15 and 16 [11]
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