Inflammatory priming predisposes mice to age-related retinal degeneration

Abstract

Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

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“…As generally reported, 40,41 the thickness of the ONL in WT mice at 10 to 12 months (n ¼ 2) is 59.1 6 5.1 lm in the center of the retina (10-12 photoreceptor rows; Fig. 3A) and 40.9 6 5.2 lm in the periphery (6-8 photoreceptor rows).…”

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

“…Eyes from 4-week-old C57BL/6J mice (The Jackson Laboratory) were enucleated and immediately processed to isolate total RNA that was used to prepare cDNA libraries for sequencing with the Illumina platform of RNA sequencing instruments (47,83). Three biological replicates were made for both whole-eye and retinal tissue to generate transcriptome data used to determine the FPKM for normalization and differential expression analyses.…”

“…Eye and retinal tissue libraries were prepared as previously described (47,83). Each mouse and human library was run on the Illumina Genome Analyzer IIx (Illumina) in the CWRU Genomics core facility using 36-79 single-end read lengths.…”

RNA-Seq: Improving Our Understanding of Retinal Biology and Disease

“…In mice, genetic background plays a role in the development of ARD. Mice on the A/J background are more susceptible to retinal degeneration than are BALB/c or B6 mice (Mustafi et al 2012). In A/J mice, transcriptome analysis of the whole eye, rather than a specific retinal tissue, revealed an increase in proinflammatory factors and a decrease in protective factors such as those involved in the oxidative stress response.…”

“…Age-related retinal degeneration (ARD) is the most common cause of vision loss (Mustafi et al 2012). It is defined as likely being caused by a myriad of factors that are both genetic and environmental (Donoso et al 2010;Hong et al 2011;Pennesi et al 2012;Sui et al 2012).…”