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Title: The role of tumour necrosis factor and interleukin-17 in macrophage activation and angiogenesis during chronic experimental autoimmune uveoretinitis
Author: Stimpson, Madeleine Louise
ISNI:       0000 0004 5915 9139
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Macrophages are highly plastic cells of the innate immune system that play critical roles in immunity, development, homeostasis and tissue repair. However, they are also key mediators of inflammation and tissue damage in many diseases including autoimmunity. Experimental autoimmune uveoretinitis (EAU) is an animal model of human noninfectious posterior segment uveitis, and provides a useful platform to dissect the mechanisms of disease and trial new therapies pre-clinically. Retinal antigen-specific CD4+ T cells orchestrate EAU, and macrophages subsequently recruited into the eye become conditioned by T-cell cytokines including Th1-derived interferon (IFN)y and Th17-derived interleukin (IL)-17. Whilst IFNy is known to classically activate macrophages in a tumour necrosis factor (TNF)-dependent manner, the effect of IL-17 on macrophage activation is less well understood. A chronic low-level of inflammation has been shown to persist after the peak of disease in EAU, and this is associated with the development of pathological angiogenesis. Macrophages are also a key component of the wound healing machinery, and over the course of disease macrophage polarisation changes from a pro-inflammatory NOS2+ phenotype, to an Arg1+VEGP phenotype associated with tissue remodelling and angiogenesis. Therefore the aims of this thesis were to investigate how the mixed cytokine environment present during EAU influences macrophage activation, and how altering macrophage activation impacts the expression of disease during the chronic stages of EAU. The data presented here demonstrate that IL-17 alone has little impact on macrophage activation, but when combined with IFNy can synergistically increase the production of the tissue damaging molecule nitric oxide. Furthermore, altering macrophage activation through the abrogation of TNFR1 signalling results in a significant reduction in infiltrating leukocytes, and this is associated with a reduction in clinical disease score during the chronic phase of EAU. There is a marked change in the retinal cytokine environment in TNFR1 -/- mice, with significantly lower levels of TNF and IL-17. This was associated with a concomitant reduction in IL-17- producing T cells, but IFNy expression is maintained. At 90 days post immunisation, expression of angiogenesis in the retina is significantly reduced in TNFR1 -/- mice. TNF, but not IL-17, can directly promote angiogenesis through the activation of endothelial cells, and can therefore contribute to both inflammatory and angiogenic pathways, highlighting the pivotal role of TNF in all stages of EAU.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available