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Review
. 2023 May 29;13(6):901.
doi: 10.3390/biom13060901.

The Role of Retinal Pigment Epithelial Cells in Age-Related Macular Degeneration: Phagocytosis and Autophagy

Zhibo Si  1 , Yajuan Zheng  1 , Jing Zhao  1
Affiliations
Review

The Role of Retinal Pigment Epithelial Cells in Age-Related Macular Degeneration: Phagocytosis and Autophagy

Zhibo Si et al. Biomolecules. .

Abstract

Age-related macular degeneration (AMD) causes vision loss in the elderly population. Dry AMD leads to the formation of Drusen, while wet AMD is characterized by cell proliferation and choroidal angiogenesis. The retinal pigment epithelium (RPE) plays a key role in AMD pathogenesis. In particular, helioreceptor renewal depends on outer segment phagocytosis of RPE cells, while RPE autophagy can protect cells from oxidative stress damage. However, when the oxidative stress burden is too high and homeostasis is disturbed, the phagocytosis and autophagy functions of RPE become damaged, leading to AMD development and progression. Hence, characterizing the roles of RPE cell phagocytosis and autophagy in the pathogenesis of AMD can inform the development of potential therapeutic targets to prevent irreversible RPE and photoreceptor cell death, thus protecting against AMD.

Keywords: age-related macular degeneration; autophagy; oxidative stress; phagocytosis; retinal pigment epithelial cell.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Smoking, obesity, age, high-fat diet, arteriosclerosis, and exposure to sunlight are known major risk factors for age-related macular degeneration (AMD). Reactive oxygen species increase in the presence of these risk factors, inducing oxidative stress and leading to the accumulation of oxidized lipids, proteins, and DNA. This process gradually evolves into degeneration and necrosis of retinal pigment epithelial cells, eventually leading to AMD. The increase of ROS and the accumulation of oxidized lipids, proteins, and DNA are indicated by black arrows, while the progression of AMD is indicated by blue arrows. AMD, age-related macular degeneration; ROS, reactive oxygen species; RPE, retinal pigment epithelium.
Figure 2
Figure 2
The phagocytic process of the photoreceptor outer segment (POS) is shown. The process of POS ingestion is transduced by integrins. The transduction of intracellular signals begins with the specific binding of macrophage c-mer tyrosine kinase (MerTK). Eventually, the intracellular inositol-1,4,5-trisphosphate (InsP3) content is increased, and InsP3 activation promotes POS ingestion. Integrin αvβ5 binds to phosphatidylserine (PtdSer) via MFG-E8, while milk fat globule-epidermal growth factor (EGF) factor 8 (MerTK) binds via growth arrest-specific protein 6 (Gas6). POS, photoreceptor outer segment; RPE, retinal pigment epithelium.
Figure 3
Figure 3
Two main autophagy pathways associated with the classical visual cycle of retinoids. The ULK1, ATG13, and FIP200 complex drives autophagy initiation. Autophagosome formation is primarily mediated by the BECN1, ATG14, and PI3K III complex with double-membrane structures provided by ATG9 vesicles. Autophagosome elongation and closure are coupled through the ATG5 and ATG15 complex. mTOR and AMPK are autophagy inhibitors and inducers, respectively. Autophagy begins with the sequestration of aging, damaged, or unnecessary cellular components, such as organelles and proteins, by double-membrane structures, forming phagophores (autophagosomes). These structures then fuse with lysosomes to form autolysosomes, where the enclosed materials are degraded by acid hydrolases and proteases, and the resulting breakdown products are released into the cytoplasm for recycling. Additionally, LC3-associated phagocytosis (LAP)—a noncanonical form of autophagy—is responsible for the degradation of photoreceptor outer segments (POS) and completion of the retinoid visual cycle. Upon initiation of phagocytosis, LAP immediately recruits ATG12, ATG5, and ATG12L1 to form a complex, as well as LC3 for lipidation. Following POS degradation, all-trans-retinol is converted to 11-cis-retinol in the RPE and transported out of the cell, completing the classical visual cycle of retinoids.
Figure 4
Figure 4
Autophagy pathways in age−related macular degeneration. Possible therapeutic targets are indicated by arrows.
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References

    1. Wong W.L., Su X., Li X., Cheung C.M.G., Klein R., Cheng C.Y., Wong T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health. 2014;2:e106–e116. doi: 10.1016/S2214-109X(13)70145-1. - DOI - PubMed
    1. Dasari B., Prasanthi J.R., Marwarha G., Singh B.B., Ghribi O. The oxysterol 27-hydroxycholesterol increases beta-amyloid and oxidative stress in retinal pigment epithelial cells. BMC Ophthalmol. 2010;10:22. doi: 10.1186/1471-2415-10-22. - DOI - PMC - PubMed
    1. Kinnunen K., Petrovski G., Moe M.C., Berta A., Kaarniranta K. Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol. 2012;90:299–309. doi: 10.1111/j.1755-3768.2011.02179.x. - DOI - PubMed
    1. Hogan M.J. Role of the retinal pigment epithelium in macular disease. Trans. Am. Acad. Ophthalmol. Otolaryngol. Am. Acad. Ophthalmol. Otolaryngol. 1972;76:384–389. - PubMed
    1. Beatty S., Koh H.-H., Phil M., Henson D., Boulton M. The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration. Surv. Ophthalmol. 2000;45:115–134. doi: 10.1016/S0039-6257(00)00140-5. - DOI - PubMed

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This study was supported by the National Natural Science Foundation of China (grant number 82000919).