Macrophages, cytokines and complement as therapeutic targets in retinal degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness amongst the Western population, with an annual cost of 350 billion dollars worldwide. This disease affects a specialised region in the central retina, the macula, where photoreceptors and the retinal pigment epithelium (RPE) cells begin to degenerate upon the onset of AMD. In the more prevalent atrophic or ‘dry’ form of AMD, gradual photoreceptor and RPE cell death leads to the formation of an expanding retinal lesion, which causes irreversible blindness over time. Although AMD pathogenesis involves multiple genetic and environmental factors, it is well understood that inflammation is highly implicated in disease progression. The recruitment of retinal microglia and macrophages, the production of cytokines and chemokines, and the deposition of complement system components are key features of atrophic AMD.

This thesis identifies retinal microglia and macrophages as therapeutic targets for slowing the progression of retinal degenerations such as AMD. In these studies, a rodent model of photo-oxidative damage is used, which recapitulates features of atrophic AMD including oxidative stress, inflammation and photoreceptor cell loss. This thesis first provides a further understanding of the role of microglia and macrophages in contributing to chronic complement activation and photoreceptor death in the degenerating retina. It is shown that locally-derived complement component 3 (C3) is a major contributor to the progression of retinal degeneration, and that microglia and macrophages are the primary source of retinal C3, in both rodent retinal degeneration and human AMD.

The recruitment of microglia and macrophages in retinal diseases is caused by increased chemokine signalling. It is demonstrated in this thesis that the use of a broad spectrum chemokine inhibitor (NR58-3.14.3) is able to ameliorate the accumulation of microglia and macrophages in the outer retina, protecting the photoreceptors from further damage. Finally, it is shown that interleukin-1β (IL-1β), a strong pro-inflammatory cytokine, is primarily produced by microglia and macrophages in retinal degeneration. Using therapeutic strategies to neutralise or inhibit IL-1β signalling, it is found that there is a decrease in both macrophage recruitment and photoreceptor loss. Collectively, these three studies implicate a major role for retinal microglia and macrophages in contributing to pro-inflammatory cytokine production and complement synthesis. This thesis demonstrates the therapeutic value of targeting microglia and macrophages as a strategy for reducing inflammation and photoreceptor loss in retinal degenerations including AMD. Show more