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Double-stranded RNA induces retinal pigment epithelium cell degeneration and inflammation

Klokman, G.; Xu, Y.; Bond, K.; Wu, X.; Schustak, J.; Mandelbaum, J.; Twarog, M.; Han, H.; Paulina, M.-K.; Coble, M.; Hayden, C.; Galarneau, J.-R.; Qiu, Y.; Esterberg, R.; Huang, Q.; Saint-Geniez, M.; Aranda, J.; Bao, Y.

2024-03-12 cell biology
10.1101/2024.03.11.584455 bioRxiv
Show 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.

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