title: Impairing autophagy in retinal pigment epithelium leads to inflammasome activation and enhanced macrophage-mediated angiogenesis.
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-1β, IL-6 and nitrite oxide. Exogenous IL-6 protects the dysfunctional RPE but IL-1β causes enhanced cell death. Furthermore, IL-1β 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 pro-angiogenic 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.
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors: Jian
authors: J
authors: Liu
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors: David A
authors: DA
authors: Copland
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Sofia
authors: S
authors: Theodoropoulou
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Hsi An Amy
authors: HA
authors: Chiu
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Miriam Durazo
authors: MD
authors: Barba
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Ka Wang
authors: KW
authors: Mak
authors: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
authors: Matthias
authors: M
authors: Mack
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors: Lindsay B
authors: LB
authors: Nicholson
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.|School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.|Institute of Ophthalmology, University College London, London, UK.|National Institute for Health Research (NIHR) Biomedical Research Centre, London, UK.
authors: Andrew D
authors: AD
authors: Dick
mesh_terms: D000818:Animals; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000276:immunology*; D018920:Coculture Techniques; D058847:Inflammasomes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology*; D008268:Macular Degeneration / Q000276:immunology* / Q000473:pathology; D051379:Mice; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000276:immunology; D012402:Rotenone / Q000494:pharmacology
chemical_list: D058847:Inflammasomes; D012402:Rotenone; D053148:Caspase 3