Liu, Jian and Copland, David A. and Theodoropoulou, Sofia and Chiu, Hsi An Amy and Barba, Miriam Durazo and Mak, Ka Wang and Mack, Matthias and Nicholson, Lindsay B. and Dick, Andrew D. (2016) Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis. SCIENTIFIC REPORTS, 6: 20639. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)Abstract
Age-related decreases in autophagy contribute to the progression of age-related macular degeneration (AMD). We have now studied the interaction between autophagy impaired in retinal pigment epithelium (RPE) and the responses of macrophages. We find that dying RPE cells can activate the macrophage inflammasome and promote angiogenesis. In vitro, inhibiting rotenone-induced autophagy in RPE cells elicits caspase-3 mediated cell death. Co-culture of damaged RPE with macrophages leads to the secretion of IL-1 beta, IL-6 and nitrite oxide. Exogenous IL-6 protects the dysfunctional RPE but IL-1 beta causes enhanced cell death. Furthermore, IL-1 beta toxicity is more pronounced in dysfunctional RPE cells showing reduced IRAK3 gene expression. Co-culture of macrophages with damaged RPE also elicits elevated levels of pro-angiogenic proteins that promote ex vivo choroidal vessel sprouting. In vivo, impaired autophagy in the eye promotes photoreceptor and RPE degeneration and recruitment of inflammasome-activated macrophages. The degenerative tissue environment drives an enhanced proangiogenic response, demonstrated by increased size of laser-induced choroidal neovascularization (CNV) lesions. The contribution of macrophages was confirmed by depletion of CCR2(+) monocytes, which attenuates CNV in the presence of RPE degeneration. Our results suggest that the interplay between perturbed RPE homeostasis and activated macrophages influences key features of AMD development.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MACULAR DEGENERATION; NLRP3 INFLAMMASOME; ENDOTHELIAL-CELLS; GANGLION-CELLS; AQUEOUS-HUMOR; EXPRESSION; DRUSEN; NEOVASCULARIZATION; BIOMARKERS; INTERLEUKIN-6; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2019 12:16 |
| Last Modified: | 12 Mar 2019 12:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2414 |
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