Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.647523
Title: The effects of neuroinflammation on the subventricular zone neurogenic compartment following Theiler's Murine Encephalomyelitis virus infection and its regulation by Galectin-3
Author: James, Rachel Elizabeth
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Abstract:
The subventricular zone (SVZ) is an adult neurogenic niche that contains multipotent stem/progenitor cells that may be a viable target for remyelination in Multiple Sclerosis. In response to demyelination, SVZ progenitors are recruited into myelin lesions. Currently, the effect of inflammation on the endogenous brain stem cell compartment remains poorly characterised. Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL/J mice, due to persistence of the virus, which models the chronic progressive form of multiple sclerosis. In contrast, virus is rapidly cleared in TMEV resistant C57BL/6 mice. This viral clearance is critically dependent on infiltration of CD4+ and CD8+ T cells during the first 3-14 days after infection, through the blood vessels and meninges. This project aimed to characterise the impact of TMEV induced inflammation on SVZ homeostasis. In both strains of mice the most pronounced and consistent inflammation in the CNS was observed in periventricular regions and in particular, the SVZ, which showed targeted infection by the TMEV virus. However, the time course and kinetics for infiltration at 3,7 and 14 days post infection have very different profiles between resistant C57BL/6 and susceptible SJL mice. Using RT-PCR arrays and ELISA I have shown that these differences in T cell infiltration to the SVZ may be due to much higher chemokine and cytokine expression levels in B6 mice. TMEV infection decreases SVZ cell proliferation and results in a loss of neuroblast numbers. Galectin-3 (Gal-3) is a β-galactoside binding protein that is constitutively expressed specifically in the SVZ. Following TMEV infection Gal-3 levels are significantly upregulated in the SVZ, with higher expression in B6 mice compared to SJL mice. Primary SVZ astrocytes secrete extracellular Galectin-3 at much higher levels than cortical astrocytes. Galectin-3 is a pro-inflammatory mediator which upon secretion is able to activate immune and inflammatory signaling events and amplify pro-inflammatory cytokine production. Both SJL and B6 Gal-3-/- KO mice have decreased expression of CCL2, CCL5 CXCL10 and CCL8 chemokines in the SVZ after TMEV infection. Deletion of Gal-3 prevents the loss of SVZ proliferation and in B6 mice decreases hematopoietic cell infiltration and enhances ectopic neuroblast emigration. These data implicate Galectin- 3 as a novel regulator of the SVZ inflammatory response and may provide a new target for regulating T cell CNS immigration in autoimmune disease.
Supervisor: Szele, Francis Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.647523  DOI: Not available
Keywords: Neuroscience ; Galectin-3 ; Theiler's ; multiple sclerosis ; neuroinflammation
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