Complement factor H regulates retinal development and its absence may establish a footprint for age related macular degeneration

Abstract

Age related macular degeneration (AMD) is the most common blinding disease in those over 60 years. In 50% of cases it is associated with polymorphisms of complement factor H (FH), implicating immune vulnerability. But such individuals may exhibit abnormal outer retinal blood flow decades before disease initiation, suggesting an early disease footprint. FH is expressed in the retinal pigmented epithelium (RPE). During development the RPE is adjacent to the site of retinal mitosis and complex regulatory interactions occur between the relatively mature RPE and retinal neuronal precursors that control the cell cycle. Here we ask if the absence of FH from the RPE influences retinal development using a mouse CFH knockout (Cfh−/−) with an aged retinal degenerative phenotype. We reveal that from birth, these mice have significantly disrupted and delayed retinal development. However, once development is complete, their retinae appear relatively normal, although many photoreceptor and RPE mitochondria are abnormally large, suggesting dysfunction consistent with premature ATP decline in Cfh−/−. Total retinal mtDNA is also reduced and these deficits are associated shortly after with reduced retinal function. Cfh−/+ mice also show significant abnormal patterns of cell production but not as great as in Cfh−/−. These results reveal that not only is FH an important player in sculpting retinal development but also that the developmental abnormality in Cfh−/− likely establishes critical vulnerability for later aged retinal degeneration.

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

“…A disruption of either mitochondria or glycolytic function can lead to a failure in the metabolic system. Loss of CFH has been associated with mitochondria impairment in retinal development in a CFH Knock-out mouse model [52] and patients carrying the CFH H402 high-risk variant present increased mitochondrial DNA damage [53]. Whether FH contributes to metabolic homeostasis of RPE cells has never been investigated.…”

A hidden footprint: embryological origins of age related macular degeneration

“…However, after retinal differentiation there are no obvious deficits. But when mitochondria are examined in the newly differentiated tissue abnormalities are obvious, matching subsequent reductions in ATP and abnormalities in the ERG [8].…”

“…To address this, Sivapathasuntharam et al [8] examined retinal development in Cfh−/− and Cfh+/− mice and showed significant disruptions at the retinal/RPE interface. However, after retinal differentiation there are no obvious deficits.…”

FHL-1 interacts with human RPE cells through the α5β1 integrin and confers protection against oxidative stress

“…Genetic variants in the CFH gene are associated with increased risk of AMD (19,20) and this is thought to be due to decreased activity of FHL-1 and FH that results in increased complement activation in the ECM, leading to a local inflammatory response, the recruitment of circulating immune cells, formation of drusen, and ultimately RPE cell death (21)(22)(23). However, recent studies have begun to identify non-canonical roles of FH and FHL-1 and the potential contribution of their dysregulation to AMD pathogenesis through inducing RPE mitochondrial dysfunction (24,25) and lipid peroxidation (26). Both FH and FHL-1 have an RGD motif on the surface of their fourth complement control protein (CCP) domain (see Figure 1b) and it has previously been demonstrated that FHL-1 can confer cell attachment activity to human epithelial and fibroblast cell lines via this RGD motif (27).…”

“…The majority of genes in these pathways were down-regulated, but any putative effect on cell cycle by FHL-1 is likely to be subtle, as there were no differences in cell numbers when comparing hTERT-RPE cells on FHL-1 and FN in the cell survival assays (when not treated with hydrogen peroxide) (Figure 7). Although there have been no previous studies on the role of FHL-1 on cell cycle control, mice deficient of full-length FH (also not expressing FHL-1) exhibit changes in the number of cells in the developing retina(25). These Cfh -/animals displayed reductions in the rate of mitosis during a critical period of retinal development directly after birth.…”