Epoxomicin, a Selective Proteasome Inhibitor, Activates AIM2 Inflammasome in Human Retinal Pigment Epithelium Cells.

Abstract

Emerging evidence suggests that the intracellular clearance system plays a vital role in maintaining homeostasis and in regulating oxidative stress and inflammation in retinal pigment epithelium (RPE) cells. Dysfunctional proteasomes and autophagy in RPE cells have been associated with the pathogenesis of age-related macular degeneration. We have previously shown that the inhibition of proteasomes using MG-132 activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome in human RPE cells. However, MG-132 is a non-selective proteasome inhibitor. In this study, we used the selective proteasome inhibitor epoxomicin to study the effect of non-functional intracellular clearance systems on inflammasome activation. Our data show that epoxomicin-induced proteasome inhibition promoted both nicotinamide adenine dinucleotide phosphate oxidase and mitochondria-mediated oxidative stress and release of mitochondrial DNA to the cytosol, which resulted in potassium efflux-dependent absence in melanoma 2 (AIM2) inflammasome activation and subsequent interleukin-1β secretion in ARPE-19 cells. The non-specific proteasome inhibitor MG-132 activated both NLRP3 and AIM2 inflammasomes and oxidative stress predominated as the activation mechanism, but modest potassium efflux was also detected. Collectively, our data suggest that a selective proteasome inhibitor is a potent inflammasome activator in human RPE cells and emphasize the role of the AIM2 inflammasome in addition to the more commonly known NLRP3 inflammasome.