Year: 2024
Type: preprint
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.
Authors: Garrett Klokman, YongYao Xu, Kyle Bond, Xiaoqiu Wu, Joshua Schustak, Jorgi Mandelbaum, Michael Twarog, Hongwei Han, Mary-Kate Paulina, Matthew Coble, Christopher Hayden, Jean-Rene Galarneau, John Demirs, Yubin Qiu, Robert Esterberg, Qian Huang, Ganesh Prasanna, Magali Saint-Geniez, Jorge Aranda, Yi Bao
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4392702033