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Felipe Pereira, Ivana Apicella, Ryan Makin, Younghee Kim, Charles Wright, Tetsuhiro Yasuma, Reo Yasuma, Shuichiro Hirahara, Shinichi Fukuda, Siddharth Narendran, Romulo Albuquerque, Benjamin Fowler, Nagaraj Kerur, Jayakrishna Ambati, Bradley Gelfand; Alu RNA exacerbates experimental choroidal neovascularization via an inflammasome-dependent pathway. Invest. Ophthalmol. Vis. Sci. 2020;61(7):5394.
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Alu RNA is a long non-coding RNA implicated in atrophic macular degeneration. Alu RNA induces RPE death via activation of the inflammasome. The purpose of this study is to determine the role of Alu RNA and inflammasome in aberrant angiogenesis using an experimental choroidal neovascularization (CNV) model.
CNV was induced by laser photocoagulation in C57BL/6J wild-type mice, or mice lacking molecular constituents of inflammasome (P2rx7–/–, Nlrp3–/–, caspase1–/–/11–/–, and Myd88–/– mice). Alu RNA or vehicle was administered by subretinal injection immediately after and adjacent to the laser injury. Intravitreous injections of inhibitors P2xr7, caspase 1, or MyD88 in wild-type mice were performed following laser injury and Alu RNA injection. CNV volume was measured after 7 days by confocal microscopy. qRT-PCR and ELISA of vascular endothelial growth factor (VEGF) were performed in mouse bone marrow-derived cells and human retinal pigment epithelial cells transfected with Alu RNA.
Alu RNA amplified the choroidal angiogenic response in response to laser injury in wild type mice but not in P2rx7–/–, Nlrp3–/–, caspase1–/–/11–/–, or Myd88–/– mice (P<0.05). Pharmacologic inhibition of P2xr7, caspase 1, or MyD88 in wild-type mice reduced the angiostimulatory effect of Alu RNA on laser CNV (P<0.05). In cells, Alu RNA stimulation increased mRNA expression and secretion of VEGF (P<0.05).
Alu RNA is capable of significantly increase VEGF release in-vitro and exacerbate experimental CNV. Genetic or pharmacologically inhibition of different inflammasome mediators were able to abrogate this Alu RNA activity. Thus, in addition to promoting RPE atrophy, Alu RNA-induced inflammasome activation may contribute to aberrant angiogenesis.
This is a 2020 ARVO Annual Meeting abstract.
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