Réka Albert1, Endre Kristóf2, Gábor Zahuczky3, Mária Szatmári-Tóth2, Zoltán Veréb1, Brigitta Oláh1, Morten C Moe4, Andrea Facskó5, László Fésüs2, Goran Petrovski6. 1. Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary; Stem Cells and Eye Research Laboratory, Department of Biochemistry and Molecular Biology, and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary. 2. Stem Cells and Eye Research Laboratory, Department of Biochemistry and Molecular Biology, and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary. 3. UD Genomed Ltd., Debrecen, Hungary. 4. Centre of Eye Research, Department of Ophthalmology, Oslo University Hospital, University of Oslo, Oslo, Norway. 5. Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary. 6. Department of Ophthalmology, Faculty of Medicine, University of Szeged, Szeged, Hungary; Stem Cells and Eye Research Laboratory, Department of Biochemistry and Molecular Biology, and MTA-DE Stem cell, Apoptosis and Genomics Research Group, University of Debrecen, Debrecen, Hungary. Electronic address: petrovski.goran@med.u-szeged.hu.
Abstract
BACKGROUND: The apopto-phagocytic gene expression patterns during clearance of dying cells in the retina and the effect of triamcinolone (TC) upon these processes have relevance to development of age-related macular degeneration (AMD). METHODS: ARPE-19 cells and primary human retinal pigment epithelium (hRPE) were induced to undergo cell death by anoikis and the clearance of these cells by living hRPE/ARPE-19 or human monocyte-derived macrophages (HMDMs) in the presence or absence of TC was quantified by flow cytometry. TaqMan low-density gene expression array determining known markers of phagocytosis and loss-of-function studies on selected apopto-phagocytic genes was carried out in HMDM engulfing anoikic cells. RESULTS: The glucocorticoid TC had a profound phagocytosis-enhancing effect on HMDM engulfing anoikic ARPE-19 or hRPE cells, causing a selective upregulation of the Mer tyrosine kinase (MERTK) receptor, while decreasing the expression of the AXL receptor tyrosine kinase and thrombospondin-1 (THSB-1). The key role of the MERTK could be demonstrated in HMDM engulfing dying cells using gene silencing as well as blocking antibodies. Similar pathways were found upregulated in living ARPE-19 engulfing anoikic ARPE-19 cells. Gas6 treatment enhanced phagocytosis in TC-treated HMDMs. CONCLUSIONS: Specific agonists of the Mertk receptor may have a potential role as phagocytosis enhancers in the retina and serve as future targets for AMD therapy. GENERAL SIGNIFICANCE: The use of Gas6 as enhancer of retinal phagocytosis via the MerTK receptor, alone or in combination with other specific ligands of the tyrosine kinase receptors' family may have a potential role in AMD therapy.
BACKGROUND: The apopto-phagocytic gene expression patterns during clearance of dying cells in the retina and the effect of triamcinolone (TC) upon these processes have relevance to development of age-related macular degeneration (AMD). METHODS: ARPE-19 cells and primary human retinal pigment epithelium (hRPE) were induced to undergo cell death by anoikis and the clearance of these cells by living hRPE/ARPE-19 or human monocyte-derived macrophages (HMDMs) in the presence or absence of TC was quantified by flow cytometry. TaqMan low-density gene expression array determining known markers of phagocytosis and loss-of-function studies on selected apopto-phagocytic genes was carried out in HMDM engulfing anoikic cells. RESULTS: The glucocorticoid TC had a profound phagocytosis-enhancing effect on HMDM engulfing anoikic ARPE-19 or hRPE cells, causing a selective upregulation of the Mer tyrosine kinase (MERTK) receptor, while decreasing the expression of the AXLreceptor tyrosine kinase and thrombospondin-1 (THSB-1). The key role of the MERTK could be demonstrated in HMDM engulfing dying cells using gene silencing as well as blocking antibodies. Similar pathways were found upregulated in living ARPE-19 engulfing anoikic ARPE-19 cells. Gas6 treatment enhanced phagocytosis in TC-treated HMDMs. CONCLUSIONS: Specific agonists of the Mertk receptor may have a potential role as phagocytosis enhancers in the retina and serve as future targets for AMD therapy. GENERAL SIGNIFICANCE: The use of Gas6 as enhancer of retinal phagocytosis via the MerTK receptor, alone or in combination with other specific ligands of the tyrosine kinase receptors' family may have a potential role in AMD therapy.
Authors: M Szatmári-Tóth; E Kristóf; Z Veréb; S Akhtar; A Facskó; L Fésüs; A Kauppinen; K Kaarniranta; G Petrovski Journal: Cell Death Dis Date: 2016-09-08 Impact factor: 8.469
Authors: M Hytti; S Andjelic; N Josifovska; N Piippo; E Korhonen; M Hawlina; K Kaarniranta; T J Nevalainen; G Petrovski; T Parkkari; A Kauppinen Journal: Sci Rep Date: 2017-11-23 Impact factor: 4.379