Retinal pigment epithelium (RPE) exosomes contain signaling phosphoproteins affected by oxidative stress
Open accessAbstract
Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness among the elderly population in the industrialized world. One of the typical features of this pathology is the gradual death of retinal pigment epithelial (RPE) cells, which are essential for maintaining photoreceptor functions and survival. The etiology is multifactorial, and oxidative stress is clearly one of the key factors involved in disease pathogenesis (Plafker, Adv. Exp. Med. Biol. 664 (2010) 447-56; Qin, Drug Dev. Res. 68 (2007) 213-225). Recent work has revealed the presence of phosphorylated signaling proteins in the vitreous humour of patients affected by AMD or other retinal diseases. While the location of these signaling proteins is typically the cell membrane or intracellular compartments, vitreous samples were proven to be cell-free (Davuluri et al., Arch. Ophthalmol. 127 (2009) 613-21). To gain a better understanding of how these proteins can be shed into the vitreous, we used reverse phase protein arrays (RPMA) to analyze the protein and phosphoprotein content of exosomes shed by cultured ARPE-19 cells under oxidative stress conditions. Seventy two proteins were shown to be released by ARPE-19 cells and compartmentalized within exosomes. Forty one of them were selectively detected in their post-translationally modified form (i.e., phosphorylated or cleaved) for the first time in exosomes. Sets of these proteins were linked together reflecting activation of pathway units within exosomes. A subset of (phospho)proteins were altered in exosomes secreted by ARPE-19 cells subjected to oxidative stress, compared to that secreted by control/non stressed cells. Stress-altered exosome proteins were found to be involved in pathways regulating apoptosis/survival (i.e, Bak, Smac/Diablo, PDK1 (S241), Akt (T308), Src (Y416), Elk1 (S383), ERK 1/2 (T202/Y204)) and cell metabolism (i.e., AMPKα1 (S485), acetyl-CoA carboxylase (S79), LDHA). Exosomes may thus represent the conduit through which membrane and intracellular signaling proteins are released into the vitreous. Changes in their (phospho)protein content upon stress conditions suggest their possible role in mediating cell-cell signaling during physio-pathological events; furthermore, exosomes may represent a potential source of biomarkers.
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RPE-derived exosomes participate in inflammatory signaling and immune modulation; exosomes released by healthy RPE decrease inflammation and downregulate the immune response, whereas exosomes released by stressed RPE promote inflammation and activate immune cells.
“a common theme that has emerged from these studies suggests that RPE-derived exosomes participate in inflammatory signaling and in immune modulation. Exosomes released by healthy RPE serve to decrease inflammation and downregulate the immune response, whereas exosomes released by stressed RPE promote inflammation and activate immune cells (Biasutto et al., 2013; Gangalum et al., 2016; Knickelbein”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Biasutto et al., 2013
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Exosomes in Ocular Health and Disease
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- Authors
- Biasutto, L., Chiechi, A., Couch, R., Liotta, L. A., & Espina, V.
- Affiliations
- University of Padua (IT)
- George Mason University (US)
- Corresponding author
- Biasutto, Lucia
- Espina, Virginia
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 319
- Issue
- 13
- Pages
- 2113-2123
- ISSN
- 0014-4827 (ISSN-L)
- PMC
- PMC3727419
- OpenAlex
- W2082325637
- Cited by
- 126
- References
- 70
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 11 · 2021: 11 · 2020: 15 · 2019: 13 · 2018: 14 · 2017: 10 · 2016: 11 · 2015: 5 · 2014: 8 · 2013: 1
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- George Mason University (1R21EY018942-01)
- Università degli Studi di Padova
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- oxidative stress, age-related macular degeneration, vitreous humor, ARPE-19 cells, apoptosis signaling, cellular metabolism, Akt signaling, ERK signaling, AMPK signaling, cell-free biomarkers, reverse phase protein array, post-translational modification
- MeSH terms
- Cells, Cultured, Humans, Models, Biological, Phosphoproteins, Reference Standards, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Protein Array Analysis, Proteomics, Retinal Pigment Epithelium, Exosomes
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