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 6

Pathway analysis of RNA-Seq differential expression profiles reveals age-related inflammatory priming in eyes of A/J mice.

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Pathway analysis of RNA-Seq differential expression profiles reveals age...
(A) Pathway analysis with Ingenuity software unveiled an aberrant inflammatory network in A/J mice characterized by priming of IFN at 1 month of age, as evidenced by increased activation of Irf7 and Stat1, coordinated increased expression of Stat1-induced secondary response genes, induction of positive regulatory loop genes in the inflammatory process, and expression of genes involved in immune cell activation. Numbers at left of each gene represent the RNA-Seq FPKM values from A/J (top; red) and B6 (bottom; black) eyes; fold differences are indicated next to the vertical arrows. (B) RT-PCR of Gbp1, Irf7, and Stat1 (shaded red in A) showed that this inflammatory priming network was preferentially exacerbated in older mice, with pronounced increases in gene product expression from 1 to 8 months of age in A/J relative to B6 mice. (C) BALB/c mice also exhibited features of inflammatory priming at 1 month of age when the same pathways were examined, but these changes were less pronounced than those in A/J mice. Numbers at left of each gene represent the RNA-Seq FPKM values from BALB/c (top; blue) and B6 (bottom; black) eyes; fold differences are indicated next to the vertical arrows. (D) RT-PCR of Gbp1, Irf7, and Stat1 (shaded blue in C) showed that in BALB/c mice, inflammatory priming was not exacerbated from 1 to 8 months of age, similar to findings in B6 mice.