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Valeria Tarallo, Yoshio Hirano, Bradley D. Gelfand, Nagaraj Kerur, Benjamin J. Fowler, Jayakrishna Ambati; Alu Rna Induced Rpe Degeneration Via Il18-myd88-caspase-3 Signaling. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6471. doi: https://doi.org/.
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Geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of people worldwide, results from death of retinal pigmented epithelium (RPE) cells. We recently identified that human eyes with GA exhibit reduced levels of DICER1 and accumulation of cytotoxic Alu repeat RNAs. Yet, it was unclear how Alu RNA caused RPE degeneration considering that it does not activate any TLR receptors. Therefore we sought to determine the mechanism of Alu induced cell-death.
The ability of Alu RNA to induce IL-18 secretion was analyzed. The effect of MyD88 knockdown to prevent RPE degeneration was tested in mice and in cell viability assay. The phosphorylation of IRAK1 and IRAK4 was assessed on western blot. Caspase 3 activation was monitored by fluorimetric assay.
Alu RNA induces IL-18 secretion by human RPE cells. In wild-type mice, intravitreous IL-18 induces RPE degeneration, and a neutralizing antibody against IL-18 protects from pAlu-induced RPE degeneration. Alu RNA does not induce degeneration in Il18r1-/- or Myd88-/- mice. Genetic or pharmacological inhibition of MyD88, which prevents phosphorylation of the IL-1R-associated kinases IRAK1 and IRAK4, protects RPE from Alu RNA-induced cytotoxicity. IL-18 induces Caspase-3 activation via a MyD88-dependent manner.
These data provide new therapeutic targets to prevent Alu RNA-induced cell death in GA.
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