Dataset Information

Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis.

ABSTRACT:

Background

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 also involved, including matrilysin/MMP-7 - an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression.

Results

Here 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.

Conclusion

Our 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.

SUBMITTER: Buhler LA

PROVIDER: S-EPMC2660336 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis.

Buhler Lillian A LA Samara Ramsey R Guzman Esther E Wilson Carole L CL Krizanac-Bengez Liljana L Janigro Damir D Ethell Douglas W DW

BMC neuroscience 20090306

<h4>Background</h4>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 also involved, including matrilysin/MMP-7 - an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression.<h4>Results</h4>Here we report that MMP-7-deficient (mmp7-/-) mice on the C57Bl/ ...[more]

PMID: 19267908

Similar Datasets

Project description:Gelatinase B/matrix metalloproteinase-9 (MMP-9) triggers multiple sclerosis (MS) and the animal model of experimental autoimmune encephalomyelitis (EAE) by the breakdown of the blood-brain barrier. Interestingly, MMP-9 is beneficial in systemic autoimmunity caused by Fas-deficiency. Fas-deficient (faslpr) and Fas-ligand-deficient mice are protected against EAE. We here investigated the interaction between Fas and MMP-9 in the setting of induction of EAE and compared short- and long-term effects. We provoked EAE with myelin oligodendrocyte glycoprotein (MOG) peptide and compared EAE development in four genotypes (wild-type (WT), single knockout mmp-9-/-, faslpr, and mmp-9-/-/faslpr) and monitored leukocytes, cytokines and chemokines as immunological parameters. As expected, faslpr mice were resistant against EAE induction, whereas MMP-9 single knockout mice were not. In the double mmp-9-/-/ faslpr mice the effects on disease scores pointed to independent rather than interrelated disease mechanisms. On a short term, after EAE induction leukocytes infiltrated into the brain and cytokine and chemokine levels were significantly higher in all the four genotypes studied, even in the faslpr and mmp-9-/-/faslpr, which did not develop clinical disease. The levels of MMP-9 but not of MMP-2 were increased in the brain and in the peripheral organs after EAE induction. After 40 days all the animals recovered and did not show signs of EAE. However, the absence of MMP-9 in the remission phase suggested a protective role of MMP-9 in the late phase of the disease, because single mmp-9-/- mice presented a delayed remission in comparison with WT animals suggesting a phase-dependent role of MMP-9 in the disease. Nevertheless, the levels of some cytokines and chemokines remained higher than in control animals even 100 days after EAE induction, attesting to a prolonged state of immune activation. We thus yielded new insights and useful markers to monitor this activated immune status. Furthermore, MMP-9 but not MMP-2 levels remained increased in the brains and, to a higher extend, in the spleens of the WT mice even during the remission phase, which is in line with the role of MMP-9 as a useful marker and a protective factor for EAE in the remission phase.

Dataset Information

Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis.

Background

Results

Conclusion

Publications

Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis.

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