| Abstract No.: | B-C2091 |
| Country: | Canada |
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| Title: | EMMPRIN-DEPENDENT MATRIX METALLOPROTEINASE INDUCTION EXAMINED IN MURINE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE) |
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| Authors/Affiliations: | 1 Smriti Agrawal*; 1 Wee Yong;
1 University of Calgary, AB, Canada
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| Content: | Objectives: Many matrix metalloproteinase (MMP) members have been implicated in detrimental roles in neuroinflammatory diseases such as multiple sclerosis (MS). However, the fact that MMP family members interact with, compensate for, and may even be inhibited by each other has made the biology of MMPs in MS a difficult one to examine. Several MMP members are simultaneously elevated in MS and in EAE, an animal model of MS, and this has added to the complexity of targeting singular or multiple MMP members in MS/EAE. The vast amounts of MMPs produced in MS and EAE are thought to be the result of the activation of many cell types in these conditions. Another possibility is that a general inducer of several MMPs is engaged during the disease process. If so, a novel approach to affect MMPs in MS could be to alter the activity of such an inducer.
The extracellular matrix metalloproteinase inducer (EMMPRIN, also known as basigin or CD147) is found on the surface of various cell types in an inactive state. When highly glycosylated leading to its activation, EMMPRIN induces fibroblasts and tumor cells to produce and activate various MMPs. Whether EMMPRIN plays a similar role in the immune system is unclear. Our specific objective is to determine a role for extracellular matrix metalloproteinase (EMMPRIN) in MMP regulation in mouse EAE.
Materials and Methods: We utilize a mouse model of experimental autoimmune encephalomyelitis (EAE), wherein MOG35-55 antigen is injected subcutaneously into C57BL/6 mice together with Fruends complete adjuvants and mycobacteria. Mice are also given two boosts of Pertussis toxin and develop a clinically paralyzing disease that proceeds posterior to anterior, with infiltration of leukocytes into the CNS parenchyma, resulting in areas of demyelination. Various tissues from these mice are dissected out and utilized in flow cytometry, histological staining, Western blotting, and gelatin zymography.
Results: We report that the activation of antigen (MOG35-55) specific T-cells in culture leads to their secretion of high levels of glycosylated EMMPRIN. In vivo, by utilizing both immunohistology and flow cytometry, we find increased numbers of EMMPRIN positive cells in the CNS of mice from the onset of EAE signs, compared to controls, and these continue to rise with disease progression. EMMPRIN immunoreactivity is detected in the CNS in both infiltrating (T-cells, macrophages) and resident (astrocytes and microglia) cellular populations. When cells are harvested temporally from the spleen/ lymph nodes and analysed by flow cytometry, the increase of EMMPRIN in leukocytes is detected in EAE animals before the appearance of clinical signs. Finally, EMMPRIN null mice, although susceptible to EAE, showed a slightly delayed onset and reduced severity in EAE disease versus wildtype controls
Conclusion: Taken together, our results indicate that the early rise of EMMPRIN is consistent with subsequent evolving pathology in EAE, and may be attributed to its role as an MMP inducer in the disease. If so, targeting EMMPRIN could help influence the marked elevation of MMPs and disease process of MS.
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