Inflammatory priming predisposes mice to age-related retinal degeneration
Debarshi Mustafi, Tadao Maeda, Hideo Kohno, Joseph H. Nadeau, Krzysztof Palczewski
Debarshi Mustafi, Tadao Maeda, Hideo Kohno, Joseph H. Nadeau, Krzysztof Palczewski
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Research Article Ophthalmology

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.

Authors

Debarshi Mustafi, Tadao Maeda, Hideo Kohno, Joseph H. Nadeau, Krzysztof Palczewski

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Figure 3

Substantial pathological changes are apparent in RPE cells of A/J mice before measurable visual decline.

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Substantial pathological changes are apparent in RPE cells of A/J mice b...
(A–J) TEM imaging of 3-month-old (A–E) A/J and (F–J) B6 retinas. (A) A/J RPE cells had an average width of 31.0 μm, with abnormal disc membrane accumulations (black arrows). (B) Ingested phagosomes in A/J mice showed (C) undigested accumulations. (D) Phagosomes were also disrupted, with (E) phagocytotic material exposed to the cytoplasm. (F) B6 RPE cells had an average width of 23.0 μm, with (G) uptake of discs that (H) were normally processed. (I) Ingested discs trafficked normally, with (J) membrane-enclosed disc elements clearly visible. Boxed regions in B, D, G, and I are shown at higher magnification in C, E, H, and J, respectively. (K) Ex vivo TPM imaging of A/J and B6 RPE cells at 1, 3, and 8 months of age. Dysmorphic features in 3-month-old A/J mice were exacerbated in 8-month-old A/J mice, but were absent in B6 mice. Boxes denote interquartile range, lines within boxes denote median, whiskers denote 10th and 90th percentiles, and symbols denote outliers. (L) RPE65 provided a localized uniform signal in 1-month-old A/J mouse retina, but a decreased and heterogeneously localized signal in 8-month-old A/J mouse retina (yellow arrows). No apparent age-related changes were noted in retinas of B6 mice. (M) Regeneration of 11-cis-retinal decreased 75% in A/J retinas by 8 months of age; no such change was noted in B6 mice. *P < 0.05. Scale bars: 5 μm (A and F); 1 μm (B, D, G, and I); 0.5 μm (C, E, H, and J); 20 μm (K and L).