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Daipayan Banerjee, Younghee Kim, Shinichi Fukuda, Reo Yasuma, Ana Bastos-Carvalho, Benjamin Fowler, Tetsuhiro Yasuma, Bradley D Gelfand, Nagaraj Kerur, Jayakrishna Ambati; Role of interferon signaling in Alu RNA-induced AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):487. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is an untreatable eye condition characterized by progressive degeneration of the retinal pigmented epithelium (RPE) and finally irreversible loss of vision. Recent studies have implicated NLRP3 inflammasome activation by Dicer1 deficit-driven Alu RNA in the pathogenies of AMD. Recently we have observed that, Dicer1 deficit/Alu RNA also induces a robust interferon signaling. The goal of our current study is to investigate the mechanistic convergence of IFN signaling and inflammasome pathways in mediating the Alu RNA-induced RPE degeneration.
We studied WT (C57Bl/6J), Ifnar-/-, Irf3-/-, Irf7-/- mice. RPE cells from mouse or humans were transfected with in vitro transcribed Alu RNA or a plasmid encoding an Alu element. DICER knockdown was achieved using anti-sense oligonucleotides against DICER. Inflammasome activation was monitored by immunoblotting for Caspase-1 or Caspase-4. Interferon signaling was monitored by assessing the phosphorylation status of STAT2.Secreted INFβ in media was accessed by ELISA. Subretinal injection of pAlu, Alu RNA or siDicer1 was used to induce RPE degeneration. RPE degeneration was assessed by fundus photography and zonula occludens-1 (ZO-1) staining of mouse RPE.
Alu stimulation of RPE cells induced secretion of IFN-beta and phosphorylation of STAT2. Furthermore mice lacking interferon regulatory factors (IRF3 and 7), Stat2-/- or IFN alpha/beta receptor (IFNAR) deficient mice were protected from Alu-mediated RPE degeneration. Interestingly Alu RNA-induced inflammasome activation was abrogated in Ifnar-/- mice.
Our findings reveal an unexpected collaboration between Type I INF signaling and inflammasome pathways in driving the Alu RNA-induced RPE degeneration in AMD.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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