Retinal pigment epithelial cells use a MerTK‐dependent mechanism to limit the phagocytic particle binding activity of αvβ5 integrin
Open accessAbstract
BACKGROUND INFORMATION: αvβ5 integrin and Mer tyrosine kinase (MerTK) receptors reside at the apical surface of the retinal pigment epithelium (RPE) in the eye to promote the diurnal, synchronised phagocytosis of shed photoreceptor outer segment fragments (POS) that is critical for vision. Phagocytosis assays studying RPE cells in culture have defined roles for αvβ5 in POS surface binding and for MerTK in engulfment of bound POS. Both receptors have thus far only been studied separately. It is therefore unknown if αvβ5 integrin activity in POS binding is independent of the engulfment function of RPE cells. This study investigates how increasing αvβ5 receptor levels affect POS binding and internalisation by wild-type (wt), αvβ5- or MerTK-deficient RPE. RESULTS: β5 integrin-green fluorescent protein (β5-GFP) fusion proteins formed heterodimeric receptors with endogenous αv integrin subunits at the apical surface of mouse or rat RPE cells that co-immunoprecipitated focal adhesion kinase and redistributed with bound POS such as endogenous αvβ5 receptors. In β5(-/-) RPE cells, de novo formation of αvβ5-GFP receptors restored POS binding and internalisation up to, but not, above wt POS uptake levels. In wt RPE cells, increasing levels of αvβ5 surface receptors by over-expressing β5-GFP only moderately stimulated POS binding, even if POS internalisation was inhibited pharmacologically or by lowering incubation temperatures. In contrast, the same increase in αvβ5 receptor levels dramatically enhanced POS binding of RPE cells lacking MerTK. Furthermore, decreasing MerTK expression by RNA interference increased POS binding to endogenous αvβ5 receptors of wt RPE cells. CONCLUSIONS: Expressing β5-GFP is sufficient to reverse phagocytic deficiencies of RPE cells derived from β5(-/-) mice, indicating that these cells do not irreversibly lose other components of the phagocytic machinery. RPE cells expressing the engulfment receptor MerTK control POS binding by limiting activity of endogenous αvβ5 and αvβ5-GFP integrins, although they reside at the apical, phagocytic surface. In contrast, RPE cells permanently or transiently losing MerTK expression lack this regulatory mechanism and bind excess POS via surface αvβ5 receptors. Taken together, these data reveal a novel feedback mechanism that restricts binding of POS to surface αvβ5 integrin receptors in RPE cells.
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The presence of the MERTK ingestion receptor limits OS binding via αvβ5 integrin, such that transient reduction of MERTK expression or use of cells lacking MERTK results in excessive OS binding.
“the presence of the MERTK ingestion receptor (discussed in the section 3.5.1) limits OS binding via αvβ5 integrin, such that transient reduction of MERTK expression or use of cells lacking MERTK results in excessive OS binding (Nandrot et al., 2012).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Nandrot et al., 2012
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The cell biology of the retinal pigment epithelium
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Self-citationMERTK interactions with SH2-domain proteins in the retinal pigment epithelium
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- Authors
- Nandrot, E. F., Silva, K. E., Scelfo, C., & Finnemann, S. C.
- Affiliations
- Cornell University (US)
- Fordham University (US)
- Corresponding author
- Finnemann, Silvia C.
- Venue
- Biology of the Cell
- Publisher
- Wiley
- Published
- 2012-03-05
- Volume
- 104
- Issue
- 6
- Pages
- 326-341
- ISSN
- 0248-4900 (ISSN-L)
- 1768-322X
- PMC
- PMC3577091
- OpenAlex
- W1972271762
- Cited by
- 52
- References
- 21
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 7 · 2014: 6 · 2013: 3
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biology of the Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Eye Institute (R01EY013295, EY-13295)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- retinal pigment epithelium, MERTK, integrin αvβ5, photoreceptor outer segment phagocytosis, engulfment, receptor internalization, focal adhesion kinase, feedback regulation, photoreceptor degeneration
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Cattle, Cell Line, Cells, Cultured, Gene Expression Regulation, Humans, Phagocytosis, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Swine, Gene Deletion, Receptors, Vitronectin, Receptor Protein-Tyrosine Kinases, Integrin beta Chains, Green Fluorescent Proteins, Mice, Rats, Focal Adhesion Protein-Tyrosine Kinases, Retinal Pigment Epithelium, Retinal Photoreceptor Cell Outer Segment
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