Retinal Changes Precede Visual Dysfunction in the Complement Factor H Knockout Mouse

Abstract

We previously reported that aged mice lacking complement factor H (CFH) exhibit visual defects and structural changes in the retina. However, it is not known whether this phenotype is age-related or is the consequence of disturbed development. To address this question we investigated the effect of Cfh gene deletion on the retinal phenotype of young and mid-age mice. Cfh −/− mouse eyes exhibited thickening of the retina and reduced nuclear density, but relatively normal scotopic and photopic electroretinograms. At 12 months there was evidence of subtle astroglial activation in the Cfh −/− eyes, and significant elevation of the complement regulator, decay-accelerating factor (DAF) in Müller cells. In the retinal pigment epithelium (RPE) of young control and Cfh −/− animals mitochondria and melanosomes were oriented basally and apically respectively, whereas the apical positioning of melanosomes was significantly perturbed in the mid-age Cfh −/− RPE. We conclude that deletion of Cfh in the mouse leads to defects in the retina that precede any marked loss of visual function, but which become progressively more marked as the animals age. These observations are consistent with a lifelong role for CFH in retinal homeostasis.

Deficiency of CC chemokine ligand 2 and decay-accelerating factor causes retinal degeneration in mice

“…Ccl2 −/− / Daf1 −/− mice also displayed higher numbers of AFFs in the subretinal space, significant upregulation of phosphorylation of p38, ERK, JNK and p65, significant increase of the expression of GRP78 and ATF4 with more intensive staining in the INL and GCL, suggesting an elevated ER stress in the mutant retina. These changes are consistent with the wide distribution of DAF in the retina, from the OPL to the GCL (Williams et al, 2013), and suggests that the phenotype associated with DAF deficiency is exacerbated when combined with CCL2 deficiency, which may increase the activity of complement pathways, and, in turn, elevate ER stress (Kunchithapautham et al, 2014; Cybulsky et al, 2002). In support of this scenario, other laboratories have shown that ER stress contributes to RPE and retinal cell degeneration in animal models of age-related macular degeneration (Libby and Gould, 2010; Salminen et al, 2010; Zhang et al, 2014) or photoreceptor degeneration caused by genetic (i.e., rhodopsin mutations including S334ter, RCS, P23H-3, and hT17M) or environmental (i.e., intensive light exposure) factors (Lin et al, 2007; Gorbatyuk and Gorbatyuk, 2013; Kroeger et al, 2012; Kunte et al, 2012; Shinde et al, 2012).…”

Exposure to the complement C5b-9 complex sensitizes 661W photoreceptor cells to both apoptosis and necroptosis

“…The requirement for protection against complement activation clearly exists in the retina since rod and cone photoreceptors in human eyes, and astroglial cells in mouse eyes have been shown to express DAF [6, 7], and we also reported that CD59a and CFH are up-regulated in the mouse neuroretina in normal ageing, again supporting the idea that complement regulation is required for maintenance of a healthy retina [8]. …”

Up-regulation of pro-angiogenic pathways and induction of neovascularization by an acute retinal light damage

“…In pathological conditions, especially when retinal degeneration occurs, the three parameters described above are affected and their amplitudes decrease 24,25 . Accordingly, we observed a remarkable deflection in a-wave ( Fig.…”