Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction

Abstract

Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFHdeficient (cfh ؊/؊ ) mice. cfh ؊/؊ animals exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the cfh ؊/؊ mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the cfh ؊/؊ mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina.age-related macular degeneration ͉ innate immunity ͉ retina

Smoke Exposure Causes Endoplasmic Reticulum Stress and Lipid Accumulation in Retinal Pigment Epithelium through Oxidative Stress and Complement Activation

“…Dysregulation of the complement system in mouse on the other hand has been associated with changes in retinal structure and function (63,64), alterations in retinal perfusion (65); but no data are available on UPR or lipid dysregulation in that context. Complement activation on RPE cells has been shown to lead to VEGF secretion followed by loss of barrier function (46,66) as well as secretion and activation of membrane metalloproteinases (58).…”

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

“…53 The connection of the complement system to AMD has been reported in some murine models of dry-type AMD. 25,44,51,52,54,57,62 Retinal abnormalities have been described in aged FH deficient (Cfh À/À ) mice. 51 However, the disease phenotype was modest because these animals displayed a partial phenotype of dry AMD.…”

“…Electron microscopy revealed that in Cfh À/À mice there was no loss of photoreceptors. 51 The authors suggested that apical secretion of FH is important in maintaining complement regulation in the retina of these mice. However, Cfh À/À mice have negligible AP activating capacity.…”

“…In these mice, the AP is almost completely inactive secondary to the fluid phase AP turnover. 51,88 Both FH (plasma protein) and CD46 (membrane bound protein) are regulators of the AP. 29,30 In mice, FH is ubiquitously present, 31,32 whereas CD46 is expressed only on spermatozoa 31,32 and in the eye.…”

Toll-like Receptor 3 Is Required for Development of Retinopathy Caused by Impaired All-trans-retinal Clearance in Mice

“…Mice with a knock-out of complement factor H (Cfh Ϫ/Ϫ ) showed only thinning of Bruch membrane, lipofuscin deposition, and disorganized photoreceptor outer segments at the advanced age of 24 months (69). Although the pathology of AMD very likely involves inflammatory reactions, the molecular mechanisms that induce them remain largely unknown.…”