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Enhanced expression of MMP-7 and MMP-9 in demyelinating multiple sclerosis lesions
J A Cossins1, J M Clements, J Ford
1British Biotech Pharmaceuticals, Oxford, UK.
Abstract:
The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease.
Insights
Matrix metalloproteinases (MMPs), specifically MMP-7 and MMP-9, are upregulated in active multiple sclerosis (MS) lesions. Their presence in macrophages and blood vessels suggests a role in MS pathology and blood-brain barrier breakdown.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Multiple sclerosis (MS) involves blood-brain barrier breakdown and immune cell infiltration into the central nervous system (CNS).
- Myelin degradation by macrophages is a hallmark of MS lesions.
- Proteinases, including matrix metalloproteinases (MMPs), may play a role in MS pathogenesis.
Purpose of the Study:
- To investigate the cellular localization and distribution of MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase) in normal human CNS and active demyelinating MS lesions.
- To determine if MMPs are specifically induced in MS lesions.
Main Methods:
- Immunohistochemistry was used to detect MMP-7 and MMP-9 protein expression in CNS tissue sections.
- Non-radioactive in situ hybridization (ISH) was performed to confirm MMP-7 gene expression.
- Tonsil and spleen tissues were used as controls for macrophage MMP-7 expression.
Main Results:
- MMP-7 immunoreactivity was weak in normal CNS microglial cells but strong in macrophages within active MS lesions.
- MMP-7 expression in macrophages was confirmed by ISH and found to be specific to MS lesions.
- MMP-9 immunoreactivity was observed in blood vessels, with increased staining in MS lesions compared to normal CNS.
Conclusions:
- MMP-7 is specifically induced in macrophages infiltrating active demyelinating MS lesions.
- MMP-9 is upregulated in blood vessels within MS lesions.
- The upregulation of MMPs in MS suggests they contribute to the disease's pathology, potentially through blood-brain barrier disruption and tissue degradation.
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