Clearance of autophagy-associated dying retinal pigment epithelial cells - a possible source for inflammation in age-related macular degeneration.
Retinal pigment epithelial (RPE) cells can undergo different forms of cell death, including autophagy-associated cell death during age-related macular degeneration (AMD). Failure of macrophages or dendritic cells (DCs) to engulf the different dying cells in the retina may result in the accumulation of debris and progression of AMD. ARPE-19 and primary human RPE cells undergo autophagy-associated cell death upon serum depletion and oxidative stress induced by hydrogen peroxide (H2O2). Autophagy was revealed by elevated light-chain-3 II (LC3-II) expression and electron microscopy, while autophagic flux was confirmed by blocking the autophago-lysosomal fusion using chloroquine (CQ) in these cells. The autophagy-associated dying RPE cells were engulfed by human macrophages, DCs and living RPE cells in an increasing and time-dependent manner. Inhibition of autophagy by 3-methyladenine (3-MA) decreased the engulfment of the autophagy-associated dying cells by macrophages, whereas sorting out the GFP-LC3-positive/autophagic cell population or treatment by the glucocorticoid triamcinolone (TC) enhanced it. Increased amounts of IL-6 and IL-8 were released when autophagy-associated dying RPEs were engulfed by macrophages. Our data suggest that cells undergoing autophagy-associated cell death engage in clearance mechanisms guided by professional and non-professional phagocytes, which is accompanied by inflammation as part of an in vitro modeling of AMD pathogenesis.
Department of Biochemistry and Molecular Biology and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary.
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Szatmári-Tóth
Department of Biochemistry and Molecular Biology and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary.
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Kristóf
Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
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Veréb
Department of Optometry, College of Applied Medicine, King Saud University, Riyadh, Saudi Arabia.
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Akhtar
Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
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Facskó
Department of Biochemistry and Molecular Biology and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary.
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Fésüs
School of Pharmacy, Facility of Health Science, University of Eastern Finland, Kuopio, Finland.
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Kauppinen
School of Pharmacy, Facility of Health Science, University of Eastern Finland, Kuopio, Finland.
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Kaarniranta
Department of Biochemistry and Molecular Biology and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary.|Stem Cells and Eye Research Laboratory, Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary.|Centre of Eye Research, Department of Ophthalmology, Oslo University Hospital, University of Oslo, Oslo, Norway.
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Petrovski
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology; D008954:Models, Biological; D018384:Oxidative Stress; D010587:Phagocytosis / Q000187:drug effects*; D061251:Primary Cell Culture; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014221:Triamcinolone / Q000494:pharmacology
D015415:Biomarkers; D016895:Culture Media, Serum-Free; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins; D014221:Triamcinolone; C025946:3-methyladenine; D002738:Chloroquine; D006861:Hydrogen Peroxide; D000225:Adenine