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Xiaodong Sun, Xueting Luo, Yiji Feng, Jian Liang; Autophagy Activated by SIRT6 Regulates Amyloid-β Induced Inflammatory Response in RPEs. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4615. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Age-associated dysfunction of retinal pigment epithelial cells (RPEs) is considered to be the initial trigger of retinal diseases such as age-related macular degeneration. Although autophagy is upregulated in RPEs during the course of aging, little is known about how autophagy is regulated and its functional role in RPEs. The purpose of this study is to determine whether Sirtuin 6 (SIRT6) contribute to regulation of autophagic and inflammatory pathways in RPEs.
Deposition of amyloid-β, and the levels of autophagy markers and SIRT6 were evaluated in the retinal sections of aging C57BL/6 mice. Two months old mice were intravitreally injected with amyloid-β1-40 at 14μg/5μL or PBS and the primary mouse RPEs were collected for examination of autophagy markers and inflammation cytokines. SIRT6 expression was inhibited using siRNA knockdown or overexpressed with plasmid transfection and the effects on expression of autophagy markers were measured by immunofluorescence and western blot. Autophagy activation was inhibited using 3-methyladenine (3-MA) and the effect on expression of inflammation cytokines was measured in with ARPE-19 cells treated after amyloid-β1-40.
In this study, we found that expression of Sirtuin 6 (SIRT6) and autophagic markers are upregulated in RPEs of aged mice where subretinal deposition of amyloid-β is accumulated and in amyloid-β stimulated RPEs. In addition, gain and loss-of-function studies confirmed the positive role of SIRT6 in regulating autophagy. Interesting, inhibition of autophagy attenuates amyloid-β stimulated inflammatory response in RPEs.
Our findings uncover the autophagy modulated by SIRT6 may be a proinflammatory mechanism for amyloid-β induced RPE dysfunction.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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