Pathways To Pathologic Retinal Iron Accumulation: Blood, Guts, And The Immune System

Iron is critical for cellular survival, as it is involved in several essential biochemical and metabolic processes. However, iron loading can cause oxidative injury through production of highly reactive hydroxyl free radicals in the Fenton reaction. Due to the danger of cellular iron overload, tight iron regulation within all tissues is essential for proper cellular function. The retina, and especially the photoreceptors, are particularly vulnerable to iron induced oxidative injury, and thus retinal iron levels are tightly regulated. Retinal iron overload has been implicated in the pathophysiology of retinal degenerative diseases, including age-related macular degeneration (AMD). The observation that iron overload occurs in a variety of neurodegenerative diseases suggests that retinal or brain iron dysregulation may play an important role in the development or exacerbation of neurodegeneration, and that the processes that promote iron accumulation within neuronal tissue, which are incompletely understood, need to be more thoroughly explored. In this thesis, the role of several iron handling proteins in regulating retinal iron homeostasis as well as the mechanisms that contribute to retinal iron dysregulation in the context of chronic neuroinflammation are explored. In Chapter 2 and 3, we investigate the role of the blood-retinal barrier (BRB) in regulating iron entry into the retina. We first investigate the role of Muller glial cells in formation of the BRB and then determine how the retinal vascular endothelial cells transport iron from the serum to the retinal parenchyma. In Chapter 4 and 5 we investigate the retina-specific role of two proteins involved in regulating iron homeostasis, hephaestin and hepcidin. In order to investigate the cell-autonomous role of iron-handling proteins in the retina, several conditional KO models were developed and the phenotypes were described. Hephaestin is a multi-copper ferroxidase is essential for both cellular iron export and oxidation of ferrous to ferric iron, while hepcidin is involved with regulation of systemic iron levels by regulating iron export through ferroportin. In chapter 6, we investigate the response of the retina to certain pro-inflammatory cytokines and describe a novel cellular iron sequestration response that may explain the link between neuroinflammation and retinal iron dysregulation