The role of complement in a new mouse model of focal retinal degeneration
Creators: name: Jiao, Helen
Publisher: name: The Australian National University
Year: 2018
Subjects: Age-related macular degeneration
retinal degeneration
complement system
classical pathway
alternative pathway
macrophage
microglia
inflammation
photo-oxidative damage

description: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss that poses a major health problem with substantial socioeconomic implications. The more prevalent form of AMD is atrophic or ‘dry’ AMD with limited treatment available. Despite the multifactorial nature of AMD pathogenesis, a key role for inflammation, which involves the recruitment of retinal microglia and macrophages and activation of the complement cascade, is the most strongly implicated of all factors in the onset of the disease. The chemokine-mediated recruitment of retinal microglia and macrophages and the complement dysregulation in AMD such as genetic polymorphisms in complement factor H (CFH), component 3 (C3) and factor B (CFB) are highly associated with the disease. The thesis explores the contributions of complement cascade in the manifestation of focal retinal degeneration, and further investigates the extent of retinal microglia and macrophages involvement as the key instigators of local complement activation. Firstly, the thesis reports on the design and implementation of a murine photo-oxidative damage model and investigates the extent to which it recapitulates several features of dry AMD, including sequential events of oxidative stress, inflammation and continuous retinal degeneration. Using this model, I then report that microglia and macrophages are the key cellular source of retinal C3 in both rodent retinal degeneration and human AMD. It is shown that locally-derived C3, synthesized by retinal microglia and macrophages, contributes to the chronic complement activation and the progression of retinal degeneration. The effects of complement activation propagated by C3 are diverse in neurodegenerative diseases, including AMD. Here, the thesis reports on the possible role of locally-derived C3 in amplifying the involvement of innate immune cells, microglia and macrophages, in focal retinal degeneration. It is shown that the absence of C3 dampens the accumulation, activation and phagocytic activity of retinal microglia and macrophages, and correlates with the reduced progression of retinal degeneration. Finally, I report on the striking divergence in temporal contributions of two pathways of complement activation – classical and alternative - during photo-oxidative damage. The findings indicate that the alternative pathway, in the form of CfB, amplifies the cascade and mediates early retinal damage, while the classical arm, through C1qa, exacerbates retinal degeneration through the engagement of NLRP3 inflammasome in myeloid cells. Neutralisation of locally-derived C1q, but not systemic complement, is able to ameliorate the progression of retinal degeneration. Collectively, this thesis describes the major contributions of complement activation, driven by retinal microglia and macrophages, in the onset and progression of retinal degeneration induced by photo-oxidative damage. The findings suggest that suppressing the capability of microglia and macrophages to elicit complement activation will serve as a potential strategy for reducing their reactivity, mitigating their contribution to retinal inflammation and degeneration.