Nucleoside reverse transcriptase inhibitors (NRTI) prevent inflammasome activation in retinal pigmented epithelium cells.

Abstract

Purpose : Geographic atrophy (GA), the untreatable form of age-related macular degeneration (AMD), the leading cause of legal blindness in aged populations globally, is characterized by loss of retinal pigmented epithelium layer (RPE). DICER1-deficit driven Alu RNA accumulation induces NLRP3 inflammasome activation, leading to RPE cell death. The purpose of this study is to investigate the efficacy of NRTIs as novel therapies for GA by blocking inflammasome activation induced by various AMD-relevant RPE stressors.

Methods : Primary human RPE cells in culture were exposed to various AMD-relevant RPE stressors namely, drusen component amyloid-beta 1-40, iron overload (Fe³⁺ ammonium citrate), cigarette smoke extract (CSE), oxidative stress inducer paraquat, double-stranded RNA Poly I:C, and sodium iodate. Cells were pre-treated with NRTIs and added again following replacement of Penicillin/Streptomycin-containing media. Inflammasome activation was monitored by immunoblotting for caspase-1 and ELISA for secreted IL-18 and IL-1B. Cell viability was monitored by MTS assay.

Results : NRTI treatment inhibited inflammasome activation (as monitored by caspase-1 immunoblotting and ELISA for IL-18 and IL-1B) induced by amyloid beta 1-40, iron-overload, cigarette smoke extract, paraquat, Poly I:C, and sodium iodate. NRTI treatment also suppressed Paraquat-induced inhibition of ARPE19 cell proliferation.

Conclusions : Our findings reveal that NRTIs attenuate inflammasome activation by six different AMD-relevant RPE stressors. Thus NRTIs are potentially promising novel therapeutic candidates for the presently incurable menace of GA.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.