Triamcinolone regulated apopto-phagocytic gene expression patterns in the clearance of dying retinal pigment epithelial cells. A key role of Mertk in the enhanced phagocytosis.

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.

• Authors: Réka Albert, Endre Kristóf, Gábor Zahuczky, Mária Szatmári-Tóth, Zoltán Veréb, Brigitta Oláh, Morten C Moe, Andrea Facskó, László Fésüs, Goran Petrovski
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1850 Issue 2 Pg. 435-46 (Feb 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25450174 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier B.V.

Chemical References

• Anti-Inflammatory Agents
• Antibodies, Neutralizing
• Eye Proteins
• Proto-Oncogene Proteins
• Triamcinolone
• MERTK protein, human
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase

Topics

• Anoikis (drug effects, genetics)
• Anti-Inflammatory Agents (pharmacology)
• Antibodies, Neutralizing (pharmacology)
• Cell Line
• Epithelial Cells (cytology, enzymology)
• Eye Proteins (biosynthesis, genetics)
• Female
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Gene Silencing (drug effects)
• Humans
• Macrophages (cytology, metabolism)
• Macular Degeneration (drug therapy, enzymology, genetics)
• Male
• Phagocytosis (drug effects, genetics)
• Proto-Oncogene Proteins (biosynthesis, genetics)
• Receptor Protein-Tyrosine Kinases (biosynthesis, genetics)
• Retinal Pigment Epithelium (cytology, enzymology)
• Triamcinolone (pharmacology)
• c-Mer Tyrosine Kinase