Inflammatory priming predisposes mice to age-related retinal degeneration
Debarshi Mustafi, … , Joseph H. Nadeau, Krzysztof Palczewski
Debarshi Mustafi, … , Joseph H. Nadeau, Krzysztof Palczewski
Published July 17, 2012
Citation Information: J Clin Invest. 2012;122(8):2989-3001. https://doi.org/10.1172/JCI64427.
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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 7

Homeostatic processing genes with decreased expression in A/J mice display protein expression in RPE and photoreceptor compartments of the retina.

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Homeostatic processing genes with decreased expression in A/J mice displ...
(A) Expression of genes of the GST, GPX, HSP, and MT families, as well as genes involved in phagosomal processing and in immune regulation, exhibited markedly decreased expression in A/J compared with both BALB/c and B6 mice. Numbers at left of each gene represent the RNA-Seq FPKM values from A/J (red), BALB/c (blue), and B6 (black) eyes; fold difference in A/J versus BALB/c (top; blue) and A/J versus B6 (bottom; black) is indicated next to each vertical arrow. Blue shading denotes genes with greater expression in BALB/c; black shading denotes genes with greater expression in B6. (B–G) IHC of 1-month-old A/J and B6 retinas was done with (B) PDE6C, cone cell marker; (C) MCOLN3, involved in lysosomal degradation; (D) GPX3, involved in ROS detoxification; (E) MYO7A, involved in protein trafficking; (F) RHO, visual pigment in rod photoreceptors; and (G) BMP4, marker of RPE cell senescence. MCOLN3, GPX3, and MYO7A staining was much more pronounced in B6 RPE (arrows in C–E). The aberrant nature of the A/J RPE cell was evidenced by mislocalization of RHO, as evidenced by signals in both the outer and inner segment (OS and IS, respectively; arrows in F) and increased expression of BMP4 in inner segment and RPE (arrows in G) in A/J mice. Scale bars: 20 μm.