Systemic Inflammation by Collagen-Induced Arthritis Affects the Progression of Age-Related Macular Degeneration Differently in Two Mouse Models of the Disease

Abstract

Purpose Age-related macular degeneration (AMD) shares similar risk factors and inflammatory responses with rheumatoid arthritis (RA). Previously, we identified increased risk for dry AMD among patients with RA compared to control subjects, using retrospective data analysis. In this current study, we investigate the role of systemic inflammation triggered in a murine model of arthritis on choroidal neovascularization and retinal pigment epithelium (RPE) degeneration mouse models. Methods Collagen-induced arthritis (CIA) was induced in C57BL/6J mice prior to laser-induced choroidal neovascularization (CNV; wet AMD model) or sodium iodate–induced retinal degeneration (NaIO 3 ; dry AMD model). CNV lesion size and retinal thickness were quantified by optical coherence photography (OCT), visual function was analyzed using optokinetic response and electroretinography, RPE morphology was examined by immunohistochemistry , and inflammatory gene expression was analyzed by quantitative PCR. Results CIA mice demonstrated decreased spatial acuity and contrast sensitivity, whereas no difference was observed in the RPE-generated c-wave. CNV lesion size was decreased in CIA mice. NaIO 3 decreased c-wave amplitude, as well as retinal thickness, which was augmented by CIA. NaIO 3 treatment resulted in loss of normal RPE hexagonal shape, which was further aggravated by CIA. Increased Cxcl9 expression was observed in the presence of CIA and CIA combined with AMD. Disease severity differences were observed between sexes. Conclusions Our data suggest systemic inflammation by CIA results in increased pathology in a dry AMD model, whereas it reduces lesions in a wet AMD model. These findings highlight the need for additional investigation into the role of secondary inflammation and sex-based differences on AMD.

Fine Tuning of an Oxidative Stress Model with Sodium Iodate Revealed Protective Effect of NF-κB Inhibition and Sex-Specific Difference in Susceptibility of the Retinal Pigment Epithelium

“…Oxidative stress plays an important role in both physiology and diseases of the RPE. To study retinal degeneration, NaIO 3 , an oxidizing agent that is exclusively toxic to the RPE, has long been used as an oxidative stress model in vivo in various mammalian species [ 12 , 13 , 14 , 17 , 21 , 24 , 25 , 43 , 52 ]. However, since most of the earlier studies were conducted with a focus on retinal degeneration by using a high dose of NaIO 3 , understanding of the detailed nature of RPE damage itself with a low dose of NaIO 3 is still limited [ 25 ].…”

“…However, sex differences under stresses have not been sufficiently studied to date. There is a report showing sex differences in the retina and RPE after NaIO 3 injection [ 43 ]. To investigate the role of systemic inflammation such as rheumatoid arthritis (RA) in AMD, the authors analyzed the effects of collagen-induced arthritis (CIA) on laser-induced CNV as a wet AMD model and NaIO 3 -induced RPE and retinal degeneration as a dry AMD model in C57BL/6J mice.…”

“…In addition, a high dose of NaIO 3 used in these studies likely masked any sex difference, if it existed at all, in the susceptibility or response to NaIO 3 between male and female animals. Due to the guidelines of US National Institutes of Health (NIH, Bethesda, MD, USA), studies of sex differences in various biological systems, including mouse RPE, have been increasingly more common recently [ 43 ]. It has been reported that age-matched male and female C57BL/6J mice show no differences in either retinal function assessed by electroretinograms (ERGs) or RPE function assessed by peak phagocytosis of photoreceptor outer segments in normal conditions [ 44 ].…”

“…It has been reported that age-matched male and female C57BL/6J mice show no differences in either retinal function assessed by electroretinograms (ERGs) or RPE function assessed by peak phagocytosis of photoreceptor outer segments in normal conditions [ 44 ]. However, few studies analyzed sex differences under stress to date, with some exceptions [ 43 ].…”

Electrophysiologic and Morphologic Strain Differences in a Low-Dose NaIO3-Induced Retinal Pigment Epithelium Damage Model

“…The consensus is that males are more susceptible than females to NaIO 3 . Schnabolk et al 26 reported that disease severity differences after NaIO 3 treatment were observed between the sexes. We chose only males to decrease and control variability.…”