Age-related macular degeneration (AMD) is a severe retinal eye disease where dysfunctional mitochondria and damaged mitochondrial DNA in retinal pigment epithelium (RPE) have been demonstrated to underlie the pathogenesis of this devastating disease. In the present study, we aimed to examine whether damaged mitochondria induce inflammasome activation in human RPE cells. Therefore, ARPE-19 cells were primed with IL-1α and exposed to the mitochondrial electron transport chain complex III inhibitor, antimycin A. We found that antimycin A-induced mitochondrial dysfunction caused caspase-1-dependent inflammasome activation and subsequent production of mature IL-1β and IL-18 in human RPE cells. AIM2 and NLRP3 appeared to be the responsible inflammasome receptors upon antimycin A-induced mitochondrial damage. We aimed at verifying our findings using hESC-RPE cells but antimycin A was absorbed by melanin. Therefore, results were repeated on D407 RPE cell cultures. Antimycin A-induced mitochondrial and NADPH oxidase-dependent ROS production occurred upstream of inflammasome activation, whereas K+ efflux was not required for inflammasome activation in antimycin A-treated human RPE cells. Collectively, our data emphasize that dysfunctional mitochondria regulate the assembly of inflammasome multiprotein complexes in the human RPE cells. The present study associates AIM2 with the pathogenesis of AMD.
Keywords: AIM2; Age-related macular degeneration; Inflammasome; Interleukin-1beta; Mitochondrial damage; NLRP3; Retinal pigment epithelium.
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