Journal Article

Regulation of age-related macular degeneration-like pathology by complement factor H

Rickman, Catherine Bowes, Toomey, Christopher B., Kelly, Una, Saban, Daniel R.

2015

Overview

Significance Age-related macular degeneration (AMD) affects approximately one-third of Americans over 70 and is characterized by lipoprotein-rich sub-retinal pigmented epithelium (sub-RPE) deposits. Substantial evidence has emerged that implicates complement factor H (CFH) in the pathogenesis of AMD. Here, we conduct an in vivo analysis to elucidate the role of CFH in AMD pathology. We show that ( i ) CFH and lipoproteins compete for binding in the sub-RPE extracellular matrix such that decreasing CFH leads to lipoprotein accumulation and sub-RPE deposit formation; and ( ii ) detrimental complement activation within sub-RPE deposits leads to RPE damage and vision loss. This new understanding of the complicated interactions of CFH in development of AMD-like pathology paves the way for identifying more targeted therapeutic strategies for AMD. Complement factor H (CFH) is a major susceptibility gene for age-related macular degeneration (AMD); however, its impact on AMD pathobiology is unresolved. Here, the role of CFH in the development of AMD pathology in vivo was interrogated by analyzing aged Cfh ⁺/⁻ and Cfh ⁻/⁻ mice fed a high-fat, cholesterol-enriched diet. Strikingly, decreased levels of CFH led to increased sub-retinal pigmented epithelium (sub-RPE) deposit formation, specifically basal laminar deposits, following high-fat diet. Mechanistically, our data show that deposits are due to CFH competition for lipoprotein binding sites in Bruch’s membrane. Interestingly and despite sub-RPE deposit formation occurring in both Cfh ⁺/⁻ and Cfh ⁻/⁻ mice, RPE damage accompanied by loss of vision occurred only in old Cfh ⁺/⁻ mice. We demonstrate that such pathology is a function of excess complement activation in Cfh ⁺/⁻ mice versus complement deficiency in Cfh ⁻/⁻ animals. Due to the CFH-dependent increase in sub-RPE deposit height, we interrogated the potential of CFH as a previously unidentified regulator of Bruch’s membrane lipoprotein binding and show, using human Bruch’s membrane explants, that CFH removes endogenous human lipoproteins in aged donors. Thus, advanced age, high-fat diet, and decreased CFH induce sub-RPE deposit formation leading to complement activation, which contributes to RPE damage and visual function impairment. This new understanding of the complicated interactions of CFH in AMD-like pathology provides an improved foundation for the development of targeted therapies for AMD.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Americans / Animals / Binding sites / Biological Sciences / Choroid - metabolism / Choroid - pathology / complement / Complement Factor H - genetics / Complement Factor H - metabolism / Complement Factor H - physiology / Diet / Diet, High-Fat / epithelium / extracellular matrix / lipoproteins / Macular degeneration / Macular Degeneration - pathology / Macular Degeneration - physiopathology / Membranes / Mice / Mice, Transgenic / Monocytes - metabolism / Monocytes - pathology / pathogenesis / Pathology / PNAS Plus / Retinal Pigment Epithelium - metabolism / Retinal Pigment Epithelium - pathology / vision