Phagocytosis of Retinal Rod and Cone Photoreceptors

Kevany, Brian M.; Palczewski, Krzysztof

doi:10.1152/physiol.00038.2009

Cited by 426Retinal Development and DisordersRetinal Diseases and TreatmentsPhagocytosis and Immune Regulation

Phagocytosis of Retinal Rod and Cone Photoreceptors

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Kevany, Brian M., Palczewski, Krzysztof·2010·Physiology

DOI 10.1152/physiol.00038.2009PMC PMC2839896

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Abstract

Photoreceptor cells maintain a roughly constant length by continuously generating new outer segments from their base while simultaneously releasing mature outer segments engulfed by the retinal pigment epithelium (RPE). Thus postmitotic RPE cells phagocytose an immense amount of material over a lifetime, disposing of photoreceptor cell waste while retaining useful content. This review focuses on current knowledge of outer segment phagocytosis, discussing the steps involved along with their critical participants as well as how various perturbations in outer segment (OS) disposal can lead to retinopathies.

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The visual pigments in rods and cones are rhodopsin and iodopsin, respectively.
“The visual pigments in rods and cones are rhodopsin (RHO) and iodopsin, respectively.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [54]
The Vertebrate Eye section (page unavailable) says rod and cone outer segments contain light-absorbing photopigments called opsins. It does not identify the rod pigment as rhodopsin or the cone pigment as iodopsin; searches for those names and the rod–cone pigment pairing found no such statement in the paper's text. (LLM, conf=0.78)
Experimental — accuracy not yet measured
A2E cannot be further metabolized and RPE cells are postmitotic, so A2E and related bisretinoids accumulate in the RPE in the form of lipofuscin deposits.
“As A2E can not be further metabolized and as RPE cells are postmitotic, A2E and related bisretinoids accumulate in the RPE in the form of lipofuscin deposits.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [54]
The OS phagocytosis section (page unavailable) says RPE cells are postmitotic and therefore cannot dilute A2E through cell division, causing A2E to build up. It says lipofuscin cannot be degraded, but does not say that A2E cannot be further metabolized or that A2E and related bisretinoids accumulate as lipofuscin deposits; it instead describes lipofuscin as being converted to A2E. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Lipofuscin compromises the function and viability of RPE cells and ultimately results in photoreceptor degeneration and a loss of vision.
“Lipofuscin is an autofluorescent cellular waste product that compromises the function and viability of RPE cells and ultimately results in photoreceptor degeneration and a loss of vision [54,69,73,74,75].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [54]
The OS phagocytosis section identifies lipofuscin as an autofluorescent waste product and says its derivative A2E is toxic to RPE cells and inhibits their degradation of photoreceptor material. It says accumulated photo-oxidized products are believed to underlie degenerative retinal disease, but also notes an alternative hypothesis about A2E. It does not establish the claimed inevitable progression from lipofuscin to photoreceptor degeneration and vision loss. (LLM, conf=0.86)
Experimental — accuracy not yet measured
In the membranes of outer photoreceptor segments, nonenzymatically formed toxic bisretinoids are converted upon phagocytosis in the acidic environment of RPE phagolysosomes to bisretinoid pyridinium compound A2E and related bisretinoids.
“In the membranes of outer photoreceptor segments are nonenzymatically formed toxic bisretinoids. Upon phagocytosis, these bisretinoids are in the acidic environment of RPE phagolysosomes converted to bisretinoid pyridinium compound A2E and related bisretinoids [54,69,70,71,72,73,74].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [54]
In “Photoreceptor Renewal > OS phagocytosis” (page unavailable), the paper says that lipofuscin formed from all-trans-retinal and phosphatidylethanolamine is converted in the RPE to A2E, a toxic pyridinium bisretinoid. The section also reports acidification of RPE phagosomes, but does not say that bisretinoids form nonenzymatically in outer-segment membranes, that acidity drives their conversion to A2E, or that related bisretinoids are produced. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Postmitotic rod and cone photoreceptors undergo daily renewal in which about 10% of outer segment volume is shed, phagocytosed by adjacent RPE cells, and replaced by new outer segments.
“postmitotic rod and cone photoreceptor cells undergo a daily regeneration process wherein ∼10% of their OS volume is shed, subsequently phagocytosed by adjacent RPE cells268 and replaced with newly formed outer segments.”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [268]

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Hayes, M., Shao, D., Grieve, A., Levine, T. P., Bailly, M., & Moss, S. (2008) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamcr.2008.10.007 · Cited by 61 · see citing works
Disc shedding and autophagy in the cone-dominant ground squirrel retina
Long, K. O., Fisher, S. K., Fariss, R. N., & Anderson, D. H. (1986) · Experimental Eye Research · doi:10.1016/s0014-4835(86)80087-2 · Cited by 55 · see citing works
Gas6 Binding to Photoreceptor Outer Segments Requires γ-Carboxyglutamic Acid (Gla) and Ca2+ and is Required for OS Phagocytosis by RPE Cells in vitro
Hall, M. O., Obin, M. S., Prieto, A. L., Burgess, B. L., & Abrams, T. A. (2002) · Experimental Eye Research · doi:10.1006/exer.2002.2030 · Cited by 43 · cited 1× · see citing works
“These -carboxylated residues have been shown to bind PS and are required for MertK activation of particle engulfment (39, 50, 63).”
Background
Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium
Hoppe, G., O'Neil, J., Hoff, H., & Sears, J. E. (2004) · Cellular and Molecular Life Sciences (CMLS) · doi:10.1007/s00018-004-4080-5 · Cited by 42 · cited 1× · see citing works
“breakdown of OS in the RPE by delaying the maturation of RPE phagosomes (48, 49).”
Background
Lipofuscin and macular degeneration.
Wolf, G. (2004) · Nutrition reviews · doi:10.1016/j.ajo.2004.04.034 · Cited by 35 · cited 1× · see citing works
“Lipofuscin in the retina, formed from the condensation of two molecules of all-transretinal and one molecule of phoshatidylethanolamine, is believed to accumulate because of incomplete digestion of OS in the RPE (79, 85).”
Background
Light stimulates in vivo inositol lipid turnover in frog retinal pigment epithelial cells at the onset of shedding and phagocytosis of photoreceptor membranes.
de Turco, E., Gordon, W. C., & Bazan, N. G. (1992) · Experimental Eye Research · doi:10.1016/0014-4835(92)90176-s · Cited by 34 · see citing works
Association of changes in intracellular cyclic AMP with changes in phagocytosis in cultured rat pigment epithelium
Edwards, R. B., & Flaherty, P. M. (1986) · Current Eye Research · doi:10.3109/02713688608995161 · Cited by 31 · cited 1× · see citing works
“The second messenger cAMP acts as an important modulator of phagocytotic activity downstream of initial signaling by InsP3/Ca 2+ (18, 36).”
Background
Protein kinase C activation by serotonin potentiates agonist-induced stimulation of cAMP production in cultured rat retinal pigment epithelial cells.
Nash, M., Wood, J. P. M., & Osborne, N. N. (1997) · Experimental Eye Research · doi:10.1006/exer.1996.0214 · Cited by 31 · see citing works
Serotonergic, 5-HT2, receptor-mediated phosphoinositide turnover and mobilization of calcium in cultured rat retinal pigment epithelium cells.
Osborne, N. N., Fitzgibbon, F., Nash, M., Liu, N., Leslie, R., & Cholewinski, A. (1993) · Vision Research · doi:10.1016/0042-6989(93)90097-g · Cited by 31 · cited 1× · see citing works
“Regulation of both InsP3/Ca 2+ and cAMP by serotonin through PKC has been demonstrated in cultured rat RPE cells (66, 67, 70).”
Background
Origin of the Vertebrate Visual Cycle†
Takimoto, N., Kusakabe, T. G., & Tsuda, M. (2007) · Photochemistry and Photobiology · doi:10.1562/2006-06-30-ir-957 · Cited by 26 · cited 1× · see citing works
“The RPE conveys new retinoids from the bloodstream and is absolutely required for the regeneration of 11-cis-retinal in a process referred to as the “visual cycle” (78, 83).”
Background
Fat(al) attraction: Oxidized lipids act as “eat‐me” signals
Fadeel, B., Quinn, P., Xue, D., & Kagan, V. (2007) · HFSP Journal · doi:10.2976/1.2800110 · Cited by 21 · cited 1× · see citing works
“During apoptosis, this asymmetry is disrupted, and PS, exposed extracellularly in patches, is thought to act as an “eat-me” signal (19).”
Background
Agonist-induced effects on cyclic AMP metabolism are affected in pigment epithelial cells of the Royal College of Surgeons rat.
Nash, M., & Osborne, N. (1995) · Neurochemistry International · doi:10.1016/0197-0186(95)00040-f · Cited by 16 · cited 1× · see citing works
“Regulation of both InsP3/Ca 2+ and cAMP by serotonin through PKC has been demonstrated in cultured rat RPE cells (66, 67, 70).”
Background
Phagocytosis in the normal and ischaemic retinal pigment epithelium of the rabbit.
Johnson, N. F. (1975) · Experimental Eye Research · doi:10.1016/0014-4835(75)90147-5 · Cited by 16 · cited 1× · see citing works
“Studies in mammals, fish, and amphibians demonstrated a highly conserved mechanism for ROS renewal (27, 51, 68, 87, 88).”
Background

Flagged first, then by citations

27 of the 101 references couldn’t be matched to a known paper.

Research works printed but not linked: 20

[2]Anderson DH Fisher SK Steinberg RH Mammalian cones: disc shedding, phagocytosis, renewal Invest Ophthalmol Vis Sci 17 117 133 1978 415019
[5]Besharse JC Hollyfield JG Turnover of mouse photoreceptor outer segments in constant light and darkness Invest Ophthalmol Vis Sci 18 1019 1024 1979 478775
[12]Chaitin MH Hall MO Defective ingestion of rod outer segments by cultured dystrophic rat pigment epithelial cells Invest Ophthalmol Vis Sci 24 812 820 1983 6345445
[13]Chang Y Finnemann SC Tetraspanin CD81 is required for the alpha v beta5-integrin-dependent particle-binding step of RPE phagocytosis J Cell Sci 120 3053 3063 2007 17684062 PMC3237194
[14]Coppolino MG Krause M Hagendorff P Monner DA Trimble W Grinstein S Wehland J Sechi AS Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fcgamma receptor signalling during phagocytosis J Cell Sci 114 4307 4318 2001 11739662
[16]Daeron M Fc receptor biology Annu Rev Immunol 15 203 234 1997 9143687
[17]Deguchi J Yamamoto A Yoshimori T Sugasawa K Moriyama Y Futai M Suzuki T Kato K Uyama M Tashiro Y Acidification of phagosomes and degradation of rod outer segments in rat retinal pigment epithelium Invest Ophthalmol Vis Sci 35 568 579 1994 8113008
[27]Fisher SK Pfeffer BA Anderson DH Both rod and cone disc shedding are related to light onset in the cat Invest Ophthalmol Vis Sci 24 844 856 1983 6683265
[33]Gregory CY Abrams TA Hall MO Stimulation of A2 adenosine receptors inhibits the ingestion of photoreceptor outer segments by retinal pigment epithelium Invest Ophthalmol Vis Sci 35 819 825 1994 8125744
[36]Hall MO Abrams TA Mittag TW The phagocytosis of rod outer segments is inhibited by drugs linked to cyclic adenosine monophosphate production Invest Ophthalmol Vis Sci 34 2392 2401 1993 7686891
[44]Herman KG Steinberg RH Phagosome degradation in the tapetal retinal pigment epithelium of the opossum Invest Ophthalmol Vis Sci 23 291 304 1982 7107157
[45]Herman KG Steinberg RH Phagosome movement and the diurnal pattern of phagocytosis in the tapetal retinal pigment epithelium of the opossum Invest Ophthalmol Vis Sci 23 277 290 1982 7107156
[46]Heth CA Marescalchi PA Inositol triphosphate generation in cultured rat retinal pigment epithelium Invest Ophthalmol Vis Sci 35 409 416 1994 8112988
[47]Heth CA Schmidt SY Protein phosphorylation in retinal pigment epithelium of Long-Evans and Royal College of Surgeons rats Invest Ophthalmol Vis Sci 33 2839 2847 1992 1526733
[48]Hoppe G Marmorstein AD Pennock EA Hoff HF Oxidized low density lipoprotein-induced inhibition of processing of photoreceptor outer segments by RPE Invest Ophthalmol Vis Sci 42 2714 2720 2001 11581220
[77]Ryeom SW Sparrow JR Silverstein RL CD36 participates in the phagocytosis of rod outer segments by retinal pigment epithelium J Cell Sci 109 387 395 1996 8838662
[78]Saari JC Biochemistry of visual pigment regeneration: the Friedenwald lecture Invest Ophthalmol Vis Sci 41 337 348 2000 10670460
[79]Sparrow JR Wu Y Kim CY Zhou J Phospholipid meets all-trans-retinal: the making of RPE bis-retinoids J Lipid Res In press PMC2803227 19666736
[88]Young RW The daily rhythm of shedding and degradation of rod and cone outer segment membranes in the chick retina Invest Ophthalmol Vis Sci 17 105 116 1978 624604
[89]Young RW A difference between rods and cones in the renewal of outer segment protein Invest Ophthalmol 8 222 231 1969 5777484

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Retinoids and Retinal Diseases
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“Finally, the RPE supports photoreceptor renewal by the daily phagocytosis of about 10% of OS volume, while the photoreceptor itself regenerates roughly the same volume each day to maintain proper OS length.(211) Failure of any of these functions often results in retinal degeneration and loss of vision ((212)).”
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“RPE phagocytoses 10% of OS discs daily and renews a complete OS in 10–15 days [40].”
Background
Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss
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Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction
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Limitations and Promise of Retinal Tissue From Human Pluripotent Stem Cells for Developing Therapies of Blindness
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Authors: Kevany, B. M., & Palczewski, K.
Affiliations: Case Western Reserve University (US)
Corresponding author: Palczewski, Krzysztof
ORCID: Palczewski, Krzysztof
Venue: Physiology
Publisher: American Physiological Society
Published: 2010-02
Volume: 25
Issue: 1
Pages: 8-15
ISSN: 0886-1714 (ISSN-L)
1548-9213
1548-9221
DOI: 10.1152/physiol.00038.2009
PMC: PMC2839896
OpenAlex: W2105465142
Cited by: 426
References: 101
Citations by year: 2026: 14 · 2025: 10 · 2024: 22 · 2023: 28 · 2022: 28 · 2021: 35 · 2020: 39 · 2019: 26 · 2018: 25 · 2017: 35 · 2016: 31 · 2015: 34 · 2014: 23 · 2013: 24 · 2012: 23
FWCI: 2.13
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Physiology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Eye Institute (EY 09339, EY-019050, R01EY019050, R01EY009339)
National Institute of Diabetes and Digestive and Kidney Diseases (DK-007319, T32DK007319)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords: photoreceptor outer segment phagocytosis, retinal pigment epithelium, rod photoreceptors, cone photoreceptors, retinopathy
MeSH terms: Animals, Humans, Phagocytes, Phagocytosis, Retinal Diseases, Signal Transduction, Retinal Rod Photoreceptor Cells, Retinal Cone Photoreceptor Cells, Retinal Pigment Epithelium

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Phagocytosis of Retinal Rod and Cone Photoreceptors

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