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Published on: August 14, 2013
Double-Stranded RNA Induces Retinal Pigment Epithelium Cell Degeneration and Inflammation
Kyle Bond1, Garrett Klokman1, YongYao Xu1
1Department of Ophthalmology, Novartis Biomedical Research, Cambridge, Massachusetts, USA.
Abstract:
RIG-I signaling has been previously implicated as a driver of inflammation to the retinal pigment epithelium (RPE) during age-related macular degeneration (AMD). Double-stranded RNA (dsRNA) is known to initiate RIG-I signaling and lead to a type I interferon response. We show through shRNA knockdown that RIG-I is essential for initiating an interferon response in iPS-RPE in response to both synthetic dsRNA-mimetic 3p-hpRNA and the double-stranded retrotransposable element Alu. Analysis of human tissue from patients suffering from AMD show accumulation of dsRNA, peaking at the geographic atrophy (GA) stage. Using a new murine model of 3p-hpRNA subretinal challenge to RPE cells, we confirmed that accumulation of dsRNA initiates a type I interferon response, as well as RPE and photoreceptor degeneration. Although RPE response to synthetic dsRNA was acute, extensive leukocyte migration was observed. The results from this study verify the importance of RIG-I signaling in regulating inflammation in the subretinal space and implicates dsRNA accumulation as a driver of AMD pathogenesis.
Insights
Double-stranded RNA accumulation drives inflammation and cell degeneration in age-related macular degeneration (AMD). RIG-I signaling is essential for this inflammatory response, highlighting a key pathway in AMD pathogenesis.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Retinal pigment epithelium (RPE) inflammation is linked to age-related macular degeneration (AMD).
- RIG-I signaling, initiated by double-stranded RNA (dsRNA), drives type I interferon responses.
- dsRNA accumulation is observed in AMD tissues, particularly at the geographic atrophy (GA) stage.
Purpose of the Study:
- To investigate the role of RIG-I signaling in RPE inflammation in response to dsRNA.
- To determine if dsRNA accumulation is a driver of AMD pathogenesis.
- To establish a murine model for studying dsRNA-induced RPE and photoreceptor degeneration.
Main Methods:
- shRNA knockdown to assess RIG-I's role in interferon response in iPS-RPE cells.
- Analysis of human AMD tissues for dsRNA accumulation.
- Subretinal challenge of a murine model with synthetic dsRNA (3p-hpRNA).
Main Results:
- RIG-I is crucial for initiating interferon responses to both synthetic dsRNA and Alu elements in iPS-RPE.
- Human AMD tissues show increased dsRNA, correlating with GA stage.
- Murine model confirmed dsRNA accumulation triggers type I interferon response, RPE degeneration, and photoreceptor loss.
- Synthetic dsRNA induced acute RPE response and significant leukocyte migration.
Conclusions:
- RIG-I signaling is vital for regulating subretinal inflammation.
- dsRNA accumulation is implicated as a key factor in the pathogenesis of AMD.
- The developed murine model effectively replicates key aspects of AMD pathology.
