Metalloproteinases (MPs) include the families of matrix metalloproteinases (MMPs) and metalloproteinase-disintegrins (ADAMS). MPs are implicated in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Both MS and EAE involve central nervous system (CNS) infiltration, microglial activation, and expression of chemokines and cytokines including CC chemokine ligand 2 (CCL2) and interferon-gamma (IFNgamma). MPs mediate cellular infiltration of the CNS parenchyma and regulate activity of chemokines and cytokines. This thesis describes studies of MPs in EAE and other animal models of neuroinflammation. / Gene expression of the majority of MPs was upregulated in the CNS of mice with EAE. In contrast, four of the six membrane-bound MMPs (MT-MMPs) were downregulated. MMP-8, MMP-10, MMP-12, ADAM-12, TIMP-1, and all MT-MMPs were selected for further analysis. Macrophages were identified as a major source of MMP-12 and the tissue inhibitor of MPs-1 (TIMP-1), and granulocytes as a major source of MMP-8. ADAM-12 was expressed primarily by T cells. All but one of the MT-MMPs were expressed by microglia, and three MT-MMPs were downregulated by microglia in EAE. Five of the MT-MMPs were downregulated in transgenic mice overexpressing IFNgamma specifically in the CNS. / MPs were also regulated in non-immune models of CNS infiltration that did not involve production of IFNgamma. After entorhinal cortex stab lesion, which results in prominent influx of leukocytes to the injured area, three MT-MMPs were significantly downregulated. In transgenic (Tg) mice that overexpress CCL2 specifically in the CNS, leukocytes spontaneously cross the endothelial basement membrane of the blood-brain barrier (BBB) and accumulate in the perivascular space surrounding CNS vessels, but the mice do not show clinical symptoms. Pertussis toxin (PTx) given intraperitoneally induced encephalopathy and weight loss in CCL2 Tg mice. This involved leukocyte migration across the glia limitans into the brain parenchyma. PTx induced expression of TIMP-1, ADAM-12 and MMPs 8 and 10 in brains of CCL2 Tg mice, whereas there was no significant change in expression of MT-MMPs. Weight loss and parenchymal infiltration induced by PTx were significantly inhibited by the broad-spectrum MP inhibitor BB-94/Batimastat. / These studies identify cellular sources of MPs in neuroinflammation and links stages of cellular CNS infiltration to distinct MP profiles.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.102738 |
| Date | January 2006 |
| Creators | Toft-Hansen, Henrik. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Microbiology and Immunology.) |
| Rights | © Henrik Toft-Hansen, 2006 |
| Relation | alephsysno: 002566064, proquestno: AAINR27850, Theses scanned by UMI/ProQuest. |
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