Abstract
Matrix metalloproteinases (MMPs) have been implicated in a variety of human diseases, including neuroimmunological disorders such as multiple sclerosis. However, the recent finding that some MMPs play paradoxical protective roles in these diseases has made necessary the detailed study of the specific function of each family member in their pathogenesis. To determine the relevance of collagenase-2 (MMP-8) in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we have performed two different analyses involving genetic and biochemical approaches. First, we have analyzed the development of EAE in mutant mouse deficient in MMP-8, with the finding that the absence of this proteolytic enzyme is associated with a marked reduction in the clinical symptoms of EAE. We have also found that MMP-8(-/-) mice exhibit a marked reduction in central nervous system-infiltrating cells and demyelinating lesions. As a second approach, we have carried out a pharmacological inhibition of MMP-8 with a selective inhibitor against this protease (IC(50) = 0.4 nM). These studies have revealed that the administration of the MMP-8 selective inhibitor to mice with EAE also reduces the severity of the disease. Based on these findings, we conclude that MMP-8 plays an important role in EAE development and propose that this enzyme may be a novel therapeutic target in human neuro-inflammatory diseases such as multiple sclerosis.
Highlights
T-cell infiltration that causes myelin sheath destruction and axonal loss [1, 2]
We report that Matrix metalloproteinases (MMPs)-8Ϫ/Ϫ mice are more resistant to EAE than their wild-type counterparts, and show a marked reduction in central nervous system (CNS)-infiltrating cells and demyelinating lesions
MMP-8Ϫ/Ϫ Mice Are More Resistant to EAE—To investigate the possible contribution of MMP-8 to the initiation and progression of EAE, wild-type and MMP-8-defimRNA levels on the y-axis are expressed relative to 18 S rRNA levels
Summary
T-cell infiltration that causes myelin sheath destruction and axonal loss [1, 2]. the origin of MS remains unclear, CD4ϩ Th1 cells are believed to be the main mediators of the autoimmune reaction [3, 4]. To quantify the different cellular profiles, sampling was systematically randomized, and two sections of the spinal cord from wild-type and MMP-8Ϫ/Ϫ immunized mice, with representative clinical scores, were selected to perform the immunohistochemical analysis.
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