Phagocytosis of outer segments by retinal pigment epithelium: phagosome-lysosome interaction
Open accessAbstract
We studied phagocytosis of rod outer segments (ROS) by the retinal pigmented epithelium (RPE) using rapid freezing, freeze-drying, and electron microscopic immunocytochemistry. Phagocytosis of photoreceptor outer segment tips by the RPE occurs daily, and in rats the shedding of these tips is light-entrained to a circadian rhythm. We studied the phagocytic process 5, 30, 90, and 150 min after light onset or after subjective light onset in rats entrained to a 12-hr dark-12-hr light cycle. Lysosomes were labeled with antibodies to cathepsin D, a major lysosomal enzyme responsible for opsin degradation. Phagosomes and phagolysosomes were recognized because of the lamellar structure of their photoreceptor-derived contents. We found a population of lysosomes that fuse with one another before they interact with phagosomes. This fusion can be triggered either by light or by endogenous circadian mechanisms. We also found that lysosome-phagosome interaction occurs after the ingestion stage is completed and that this interaction occurs in two steps. First, smaller lysosomes fuse with phagosomes. Subsequently, larger lysosomes appear to interact with phagosomes via pore-like or bridge-like structures. It is proposed that interchange of contents takes place through these structures.
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Bridge-like structures were described between phagosomes and organelles thought to be lysosomes in the rat RPE as early as 30 min after light onset.
“‘Bridge-like structures’ were described between phagosomes and organelles thought to be lysosomes in the rat RPE as early as 30 min after light onset (Bosch et al., 1993).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Bosch et al., 1993
In RPE-J cells, engulfed POS co-localize with LAMP1, LAMP2, and cathepsin D, indicating that POS degradation proceeds.
“Indeed, we observed that in RPE-J cells engulfed POS co-localized with LAMP1, LAMP2, and cathepsin D (Figure 5A, left panels, arrows) indicating that POS degradation was proceeding (Bosch et al., 1993; Rakoczy et al., 1997; Ramkumar et al., 2010).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Bosch et al., 1993
In normal RPE cells, POS are contained in single membrane phagosomes.
“In normal RPE cells POS were contained in single membrane phagosomes as reported (Bosch et al., 1993; Gordiyenko et al., 2010; Strauss, 2005).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Bosch et al., 1993
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The Retinal Pigment Epithelium in Visual Function
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“It has been proposed that the rate of phagocytosis is dependent on the rate in which apical POS phagocytosis receptor containing cell membrane cycles between the extracellular and intracellular space (79).”
BackgroundThe retinal pigment epithelium: a versatile partner in vision
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“Lysosomal fusion can be triggered by both light and circadian mechanism s (Bosch et al., 1993).”
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“Another function in the maintenance of photoreceptor excitability is the phagocytosis of shed photoreceptor outer segments [68–70].”
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“‘Bridge-like structures’ were described between phagosomes and organelles thought to be lysosomes in the rat RPE as early as 30 min after light onset (Bosch et al., 1993).”
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“Indeed, we observed that in RPE-J cells, engulfed POS colocalized with LAMP1, LAMP2, and cathepsin D (Figure 5A, arrows in left panels), indicating that POS degradation was proceeding (Bosch et al., 1993; Rakoczy et al., 1997; Ramkumar et al., 2010).”
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“Given this location, the RPE plays critical roles in the maintenance of the POS, in part by removing shed rod and cone debris(12); once endocytosed by endosome formation, this debris is ultimately degraded in lysosomes.(13) It has been proposed that abnormalities in lysosome-dependent degradation of shed POS debris ca…”
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“The larger lysosomes appear to interchange their contents with phagolysosomes through pore-like or bridge-like structures (Bosch et al., 1993).”
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“POS digestion is mediated in the endo-lysosomal compartments (Bosch et al., 1993; Deguchi et al., 1994).”
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“Similar to during the general process of phagocytosis, engulfed shed POS are enclosed by cellular membranes forming phagosomes, followed by fusion with lysosomes which formed phagolysosomes, and then degraded by lysosomal enzymes (Bosch, Horwitz, and Bok 1993).”
BackgroundMultimodal Imaging in Ocular Sarcoidosis
Mahendradas, P., Maruyama, K., Mizuuchi, K., et al. (2020) · Ocular Immunology and Inflammation · doi:10.1080/09273948.2020.1751210 · Cited by 28 · see citing works
Lipofuscin and the Principles of Fundus Autofluorescence: A Review
Nandakumar, N., Buzney, S. M., & Weiter, J. J. (2012) · Seminars in Ophthalmology · doi:10.3109/08820538.2012.711415 · Cited by 28 · see citing works
Phagosomal and mitochondrial alterations in RPE may contribute to KCNJ13 retinopathy
Toms, M., Burgoyne, T., Tracey‐White, D., Richardson, R., Dubis, A. M., Webster, A. R., Futter, C. E., & Moosajee, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-40507-8 · Cited by 29 · see citing works
Paraoan, L. (2001) · Molecular Membrane Biology · doi:10.1080/09687680110075101 · Cited by 28 · see citing works
Rakoczy, P. E., Lai, M. C., WATSON, M., et al. (1996) · Antisense and Nucleic Acid Drug Development · doi:10.1089/oli.1.1996.6.207 · Cited by 28 · see citing works
“This project serves to study the uptake, distribution, persistence, and stability of a fluorescein-labeled oligonucleotide in the retina and to investigate the effect of an antisense oligonucleotide, complementary to cathepsin S, on the accumulation of POS-derived debris in a longitudinal study.”
InfluentialKarg, M. M., Moorefield, M., Hoffmann, E., Philipose, H., Krasniqi, D., Hoppe, C., Shu, D. Y., Shirahama, S., Ksander, B. R., & Saint-Geniez, M. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00358-4 · Cited by 27 · see citing works
“5 (See legend on previous page.) cell function and may predispose the aging aye to AMD development [25–27].”
BackgroundBipolar assembly of caveolae in retinal pigment epithelium
Mora, R. C., Bonilha, V. L., Shin, B., Hu, J. G., Cohen‐Gould, L., Bok, D., & Rodriguez-Boulan, E. J. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00405.2005 · Cited by 28 · see citing works
“The RPE also performs phagocytosis and digestion of old photoreceptor outer segments (3, 56).”
BackgroundSelf-citationRegulation of the rhythmic diversity of daily photoreceptor outer segment phagocytosis in vivo
Moran, A. L., Fehilly, J. D., Jones, D. F., Collery, R. F., & Kennedy, B. N. (2022) · The FASEB Journal · doi:10.1096/fj.202200990rr · Cited by 27 · see citing works
Pan, H.-Y., Alamri, A. H., & Valapala, M. (2019) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-019-0159-8 · Cited by 23 · see citing works
Retinal light damage: From mechanisms to protective strategies
Zhang, Z., Shan, X., Li, S., Chang, J. S., Zhang, Z., Dong, Y., Li, W., & Liang, F. (2024) · Survey of Ophthalmology · doi:10.1016/j.survophthal.2024.07.004 · Cited by 24 · see citing works
Changes in Retinal Pigment Epithelial Gene Expression Induced by Rod Outer Segment Uptake
Chowers, I., Kim, Y., Farkas, R. H., Gunatilaka, T. L., Hackam, A. S., Campochiaro, P. A., Finnemann, S. C., & Zack, D. J. (2004) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.03-0863 · Cited by 24 · see citing works
Bhat, S., & Gangalum, R. K. (2011) · Communicative & Integrative Biology · doi:10.4161/cib.17610 · Cited by 24 · see citing works
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Ikarashi, R., Akechi, H., Kanda, Y., Ahmad, A., Takeuchi, K., Morioka, E., Sugiyama, T., Ebisawa, T., Ikeda, M., & Ikeda, M. (2017) · Scientific Reports · doi:10.1038/srep44175 · Cited by 22 · see citing works
In vivo and in vitro monitoring of phagosome maturation in retinal pigment epithelium cells
Esteve-Rudd, J., Lopes, V. S., Jiang, M., & Williams, D. S. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3209-8_11 · Cited by 22 · see citing works
A novel melano-lysosome in the retinal epithelium of rhesus monkeys
Gouras, P., Brown, K. R., Ivert, L., & Neuringer, M. D. (2011) · Experimental Eye Research · doi:10.1016/j.exer.2011.10.011 · Cited by 19 · see citing works
“This pattern has also been reported in rat (Bosch et al., 1993).”
Dysfunctional peroxisomal lipid metabolisms and their ocular manifestations
Chen, C. T., Shao, Z., & Fu, Z. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.982564 · Cited by 19 · see citing works
“The sheded outer segments are ingested by RPE via phagocytosis and packaged into membrane-bound phagosomes, which are then fused with lysosomes for subsequent degradation (Bosch et al., 1993; Ferrington et al., 2016).”
BackgroundA role for vitamin A in the formation of ocular lipofuscin
Wassell, J., & Boulton, M. (1997) · British Journal of Ophthalmology · doi:10.1136/bjo.81.10.911 · Cited by 19 · see citing works
Oligomeric Aβ1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function
Lynn, S. A., Johnston, D. A., Scott, J. A., Munday, R., Desai, R. S., Keeling, E., Weaterton, R., Simpson, A. P., Davis, D., Freeman, T., et al. (2021) · Cells · doi:10.3390/cells10020413 · Cited by 18 · see citing works
“This contrasts with the more measured enzymatic response to POS cargos, which occur on a daily basis in RPE cells [36,40,73].”
ResultAutophagy in dry AMD: A promising therapeutic strategy for retinal pigment epithelial cell damage
Zhang, Z., Liang, F., Chang, J., Shan, X., Yin, Z., Li, W., & Li, S. (2024) · Experimental Eye Research · doi:10.1016/j.exer.2024.109889 · Cited by 15 · see citing works
Mao, Y., & Finnemann, S. C. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-17121-0_95 · Cited by 16 · see citing works
“somes (Bosch et al. 1993); (2) their increased abundance at the time POS phago-”
InfluentialFundus autofluorescence applications in retinal imaging
Lanzetta, P., Gabai, A., & Veritti, D. (2015) · Indian Journal of Ophthalmology · doi:10.4103/0301-4738.159868 · Cited by 16 · see citing works
“The byproducts of this process are stored in lysosome residual bodies as LF. [6,7] LFs are ubiquitous lipoproteic pigments accumulating in postmitotic cells in nervous, myocardial and retinal cells during ageing.”
Contribution of Membrane Trafficking Perturbation to Retinal Toxicity
Khoh‐Reiter, S., Sokolowski, S. A., Jessen, B. A., Evans, M. G., Dalvie, D., & Lu, S. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv059 · Cited by 15 · see citing works
Carter, S. P., Moran, A. L., Matallanas, D., McManus, G., Blacque, O. E., & Kennedy, B. N. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00136 · Cited by 14 · see citing works
“In the intervening years, some pathways involved in phagocytosis and subsequent degradation of shed disks in the RPE were elucidated (Bosch et al., 1993; Gibbs et al., 2003; Law et al., 2009; Jiang et al., 2015).”
BackgroundPrph2 disease mutations lead to structural and functional defects in the RPE
Tebbe, L., Sakthivel, H., Makia, M. S., Kakakhel, M., Conley, S. M., Al‐Ubaidi, M. R., & Naash, M. I. (2022) · The FASEB Journal · doi:10.1096/fj.202101562rr · Cited by 14 · see citing works
- Authors
- Bosch, E., Horwitz, J., & Bok, D.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- Journal of Histochemistry & Cytochemistry
- Publisher
- SAGE Publications
- Published
- 1993-02
- Volume
- 41
- Issue
- 2
- Pages
- 253-263
- ISSN
- 0022-1554 (ISSN-L)
- 1551-5044
- OpenAlex
- W1987319020
- Cited by
- 147
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 4 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 11 · 2014: 9 · 2013: 5 · 2012: 7
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Histochemistry & Cytochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (EY-00444, EY-00331, EY3897)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- phagocytosis, rod outer segments, retinal pigment epithelium, lysosome fusion, phagolysosomes, cathepsin D, circadian rhythm, light entrainment, photoreceptors, lysosomal enzymes
- MeSH terms
- Animals, Circadian Rhythm, Freeze Drying, Freezing, Light, Lysosomes, Models, Biological, Phagocytosis, Phagosomes, Pigment Epithelium of Eye, Rod Cell Outer Segment, Microscopy, Immunoelectron, Rats
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