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Title: The roles of myeloid derived cells in retinal inflammation and inflammation-mediated retinal angiogenesis
Author: Zhao, J.
ISNI:       0000 0004 5369 7462
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Intraocular inflammation encompasses a diverse group of diseases which account for up to 20% of severe vision loss, particularly following pathological neovascularisation in the retina. Nowadays, the use of corticosteroids is still the main armamentarium to manage these devastating conditions. Clearly safer, more target-specific and effective drugs are needed. Experimental autoimmune uveoretinitis (EAU) is an animal model for human intraocular inflammation. It is well known that myeloid derived cells substantially contribute to the pathological activities in this model. The aims of my PhD project were: to understand how myeloid-derived cells contribute to retinal damage in the EAU and to investigate whether modulating these cells can control retinal inflammation and associated retinal angiogenesis. Firstly, we showed that the deletions of both CCL2 and CX3CR1 resulted in reduced retinal inflammation in EAU. In the CCL2/CX3CR1 double knockout EAU mice, the macrophage infiltration was reduced and the inflammation was dominated by neutrophils at the acute stage. A reduction in macrophage infiltration was associated with reduced retinal angiogenesis at the chronic stage of EAU. Secondly, we found that SOCS3 in myeloid cells played an important role in EAU. The LysM-Cre-SOCS3f11f1 mice had an earlier onset and more severe retinal inflammation after immunisation. LysM-Cre-SOCS3f11f1 EAU mice also developed more severe retinal angiogenesis. Inflammation in the LysM-Cre-SOCS3f11f1 EAU mice was characterised by enhanced neutrophil infiltration and greatly increased cytokine expressions. In addition, the bone marrow-derived macrophages from LysM-Cre-SOCS3f11fl mice expressed M2 makers and produced more IL-10 and VEGF-A compared to the cells from wr mice. Finally, we found that blocking CCL2 or VEGF-A alone was not sufficient to suppress chronic inflammation-mediated retinal angiogenesis. However, systemic inhibition of arginase-1 activity was effective in reducing chronic EAU induced retinal angiogenesis. Thus, arginase inhibition could be a novel therapeutic strategy to control retinal neovascularisation related to long-standing uveoretinitis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available