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Ahmad Al Moujahed, Bo Tian, Joan W Miller, Haijiang Lin, Demetrios G. Vavvas; Absent in Melanoma 2 (AIM2) Recognizes Cytosolic DNA and Mediates Inflammation in RPE Cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):601.
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© ARVO (1962-2015); The Authors (2016-present)
Chronic inflammation plays an important role in the pathogenesis of Age-related Macular Degeneration (AMD). We have recently reported that mitochondrial DNA (mtDNA) has pro-inflammatory properties in Retinal Pigment Epithelium (RPE) cells, suggesting inflammation as a plausible link between mitochondria damage and AMD. We have also found that damaged nuclear DNA (nDNA) has similar pro-inflammatory characteristic. However, it is unknown how this DNA is recognized by RPE cells to induce inflammation. In this study, we examined the role of multiple DNA sensors and found that Absent in Melanoma 2 (AIM2), a DNA sensor that triggers the assembly of AIM2 inflammasome, mediates the pro-inflammatory effects of both mtDNA and nDNA in RPE cells.
Both human primary RPE cells and ARPE-19 cells were used. Expression of AIM2 was checked with Western blotting. The effect of ectopic DNA was checked after transfection with 1ug/ml mtDNA or nDNA for 24 hours in cells that were pre-treated with scramble- or AIM2-siRNA. Inflammatory cytokines and key cellular signaling were examined in culture medium and cell lysates using western blot.
Both human primary RPE cells and ARPE-19 cell line expressed AIM2. Both mtDNA and nDNA activated AIM2 and induced the secretion of IL-6 and IL-8, pro-IL1β and pro-caspase1. Knockdown of AIM2 by siRNA decreased the levels of secreted IL-6 and IL-8 and the protein levels of pro-IL1β and pro-caspase1. Moreover, knockdown of AIM2 inhibited the activation of NF-kB pathway that is induced by mtDNA or nDNA, suggesting that AIM2 is an upstream molecule that mediates the activation of NF-kB by cytosolic DNA in RPE cells.
AIM2 recognizes cytosolic mtDNA and nDNA and its knockdown abrogates the inflammatory phenotype that is induced by DNA in ARPE-19 cells, indicating a possible role for nucleic acids recognition in AMD, similar to some other neurodegenerative conditions. This also suggests AIM2 as an interesting therapeutic target to explore for modulating innate immune defenses in RPE.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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