Regulation of Retinal Photoreceptor Phagocytosis in a Diurnal Mammal by Circadian Clocks and Ambient Lighting

Bobu, Corina; Hicks, David

doi:10.1167/iovs.08-3145

Cited by 58 publications

(61 citation statements)

References 33 publications

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“…The process of phagocytosis exhibits a circadian rhythm (Lavail, 1976; Besharse et al, 1977; Young, 1977 & 1978; O’Day and Young, 1978; Fisher et al, 1983; Immel and Fisher, 1985; Bobu and Hicks, 2009) and can be divided into five distinct stages: 1) recognition and attachment of the OS; 2) ingestion of the OS; 3) formation of the phagosome, (4) fusion with lysosomes; and finally, 5) digestion (Figure 1). It is now recognized that abnormalities at any stage of this process or to the phagocytosis machinery can lead to disease, ranging from early-onset retinal dystrophies, such as retinitis pigmentosa or Usher’s syndrome to aging diseases affecting the central retina, such as AMD (Nandrot, 2014).…”

Section: 0 Phagocytosis In the Retinal Pigment Epithelial Cellsmentioning

confidence: 99%

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Ferrington

Sinha

Kaarniranta

2016

Progress in Retinal and Eye Research

199

229

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Maintenance of protein homeostasis, also referred to as “Proteostasis”, integrates multiple pathways that regulate protein synthesis, folding, translocation, and degradation. Failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to age-related macular degeneration (AMD). This review covers the major degradative pathways (ubiquitin-proteasome and lysosomal involvement in phagocytosis and autophagy) in the retinal pigment epithelium (RPE) and summarizes evidence of their involvement in AMD. Degradation of damaged and misfolded proteins via the proteasome occurs in coordination with heat shock proteins. Evidence of increased content of proteasome and heat shock proteins in retinas from human donors with AMD is consistent with increased oxidative stress and extensive protein damage with AMD. Phagocytosis and autophagy share key molecules in phagosome maturation as well as degradation of their cargo following fusion with lysosomes. Phagocytosis and degradation of photoreceptor outer segments ensures functional integrity of the neural retina. Autophagy rids the cell of toxic protein aggregates and defective mitochondria. Evidence suggesting a decline in autophagic flux includes the accumulation of autophagic substrates and damaged mitochondria in RPE from AMD donors. An age-related decrease in lysosomal enzymatic activity inhibits autophagic clearance of outer segments, mitochondria, and protein aggregates, thereby accelerating the accumulation of lipofuscin. This cumulative damage over a person’s lifetime tips the balance in RPE from a state of para-inflammation, which strives to restore cell homeostasis, to the chronic inflammation associated with AMD.

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Section: 0 Phagocytosis In the Retinal Pigment Epithelial Cellsmentioning

confidence: 99%

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Ferrington

Sinha

Kaarniranta

2016

Progress in Retinal and Eye Research

199

229

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“…Since structurally identifiable phagosomes persist for several hours within the RPE cytoplasm, as a consequence positive scoring of phagocytic activity is seen for protracted periods. On the contrary, immunodetection-based methods give narrower peaks since the epitopes are degraded rapidly by proteases active within the phagosomes [279]. Immunocytochemical techniques are also mostly employed in culture studies, for their rapidity and simplicity.…”

Section: The Phagocytic Function Of the Rpementioning

confidence: 99%

“…Effects of constant light (LL) have also been investigated, demonstrating that the shedding peak is abolished rapidly [292]. In the Nile Rat, LL induced complete loss in rhythmicity of rod and cone PR phagocytosis, which instead showed a broadly uniform activity [279]. In addition cone but not rod PR phagocytosis was strongly up-regulated, perhaps linked to the constant activation of the former by ambient light levels.…”

Section: The Phagocytic Function Of the Rpementioning

confidence: 99%

The Retinal Pigment Epithelium in Health and Disease

Sparrrow¹,

Hicks²,

Hamel³

2010

CMM

533

461

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Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.

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“…15 At the same time, it has been well established that physiological light exposure is implicated in the initiation and promotion of OS shedding by photoreceptor cells, and the shed OS are phagocytosed by RPE cells. [16][17][18][19][20][21] Based on this previous evidence, we speculated that exposure to IPL could increase VEGF expression in mouse RPE in vivo. VEGF protein produced in RPE is released basolaterally into the choroidal vasculature, an event implicated in both the maintenance of the choroidal vasculature 16,22 and the pathological CNV.…”

Section: Ipl Upregulates Vegf Expression In Rpe Of Wt Micementioning

confidence: 91%

Intense Physiological Light Upregulates Vascular Endothelial Growth Factor and Enhances Choroidal Neovascularization via Peroxisome Proliferator-Activated Receptor γ Coactivator-1α in Mice

Ueta

Inoue

Yuda

et al. 2012

ATVB

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Objectives— Toxicity of intense light to facilitate the development of neovascular age-related macular degeneration has been a health concern although the mechanism remains unclear. Methods and Results— Effects of intense, but within physiological range, light on retinal pigment epithelium, a major pathogenic origin of age-related macular degeneration were studied in mice. Intense physiological light upregulated vascular endothelial growth factor (VEGF) expression in retinal pigment epithelium, independent of circadian rhythm, which resulted in enhancement of choroidal neovascularization. In rd1/rd1 mice or Crx −/− mice that do not possess outer segment structure, light exposure did not induce VEGF, indicating that VEGF upregulation by light depended on increased outer segment phagocytosis by retinal pigment epithelium. In retinal pigment epithelium cells phagocytosing increased amount of outer segment, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) not hypoxia-inducible factor-1α was induced, leading to VEGF upregulation. The VEGF upregulation and choroidal neovascularization enhancement were abrogated in PGC-1α −/− mice and estrogen-related receptor-α −/− mice, indicating the involvement of PGC-1α/estrogen-related receptor-α pathway. Conclusions— Intense physiological light is involved in choroidal neovascularization through excess outer segment phagocy-tosis and VEGF upregulation mediated by PGC-1α in vivo.

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Regulation of Retinal Photoreceptor Phagocytosis in a Diurnal Mammal by Circadian Clocks and Ambient Lighting

Abstract: These data are the first to measure photoreceptor phagocytosis in a diurnal mammal under different lighting conditions and to highlight the disruptive effects of constant light, especially on cone photoreceptor function.

Cited by 58 publications

References 33 publications

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration

The Retinal Pigment Epithelium in Health and Disease

Intense Physiological Light Upregulates Vascular Endothelial Growth Factor and Enhances Choroidal Neovascularization via Peroxisome Proliferator-Activated Receptor γ Coactivator-1α in Mice

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