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 5

RNA-Seq of 3 individual biological replicates of 1-month-old A/J, BALB/c and B6 mouse eyes reveals differential transcriptome profiles.

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RNA-Seq of 3 individual biological replicates of 1-month-old A/J, BALB/c...
(A) Left: Plot of log FPKM from A/J and B6 runs. The most highly expressed transcripts common to both A/J and B6 eyes were the lens crystallin genes (outlined) and rod photoreceptor genes such as Gnat1, Rho, and Sag. Most genes highly differentially expressed in the A/J eye relate to inflammation (red), whereas genes with the lowest differential expression in the A/J eye encode homeostatic proteins (black). Right: Whereas 12,672 genes had similar expression, 332 were differentially expressed by at least 2-fold (P ≤ 0.05) between A/J and B6 eyes. (B) Examination of all 3 mouse eye transcriptomes revealed those genes exclusively more highly expressed in a single mouse strain compared with the other 2 strains, and those sharing increased expression with respect to the third strain. For example, 235 genes are exclusively more highly expressed in the B6 eye; this strain shares 26 genes also highly expressed in the A/J eye and 56 also higher in the BALB/c eye. Importantly, a large cohort of inflammatory genes exhibits increased expression in A/J mice. Interestingly, although both A/J and BALB/c eyes share increased expression of inflammatory genes, only BALB/c exhibits a counteracting increased expression of retinal homeostatic and immune regulatory genes, either exclusively or shared with B6 eyes.