Local photoreceptor cell death differences in the murine model of retinal detachment

AbstractTo investigate local cell death differences in the attached and detached retina at different regions in a murine experimental retinal detachment model. Subretinal injection of sodium hyaluronate was performed in eight-week-old C57BL/6J mice. Retinal regions of interest were defined in relation to their distance from the peak of the retinal detachment, as follows: (1) attached central; (2) attached paracentral; (3) detached apex; and (4) detached base. At day 0, the outer nuclear layer cell count for the attached central, attached paracentral, detached apex, and detached base was 1247.60 ± 64.62, 1157.80 ± 163.33, 1264.00 ± 150.7, and 1013.80 ± 67.16 cells, respectively. There were significant differences between the detached base vs. attached central, and between detached base vs. detached apex at day 0. The detached apex region displayed a significant and progressive cell count reduction from day 0 to 14. In contrast, the detached base region did not show progressive retinal degeneration in this model. Moreover, only the detached apex region had a significant and progressive cell death rate compared to baseline. Immediate confounding changes with dramatic differences in cell death rates are present across regions of the detached retina. We speculate that mechanical and regional differences in the bullous detached retina can modify the rate of cell death in this model.

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Mammalian STE20-like kinase 2, not kinase 1, mediates photoreceptor cell death during retinal detachment

Cell Death and Disease ◽

10.1038/cddis.2014.218 ◽

2014 ◽

Vol 5 (5) ◽

pp. e1269-e1269 ◽

Cited By ~ 21

Author(s):

H Matsumoto ◽

Y Murakami ◽

K Kataoka ◽

H Lin ◽

K M Connor ◽

...

Keyword(s):

Cell Death ◽

Retinal Detachment ◽

Photoreceptor Cell

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Edaravone, an ROS Scavenger, Ameliorates Photoreceptor Cell Death after Experimental Retinal Detachment

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.10-6797 ◽

2011 ◽

Vol 52 (6) ◽

pp. 3825 ◽

Cited By ~ 38

Author(s):

Mi In Roh ◽

Yusuke Murakami ◽

Aristomenis Thanos ◽

Demetrios G. Vavvas ◽

Joan W. Miller

Keyword(s):

Cell Death ◽

Retinal Detachment ◽

Photoreceptor Cell ◽

Ros Scavenger

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Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

PLoS ONE ◽

10.1371/journal.pone.0239108 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0239108

Author(s):

Ryo Terauchi ◽

Hideo Kohno ◽

Sumiko Watanabe ◽

Saburo Saito ◽

Akira Watanabe ◽

...

Keyword(s):

Cell Death ◽

Retinal Degeneration ◽

Photoreceptor Cell ◽

Fluorescent Protein ◽

Outer Nuclear Layer ◽

Inhibitory Effect ◽

Subretinal Space ◽

Photoreceptor Degeneration ◽

Retinal Inflammation ◽

Green Fluorescent

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

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Retinal Detachment Model in Rodents by Subretinal Injection of Sodium Hyaluronate

Journal of Visualized Experiments ◽

10.3791/50660 ◽

2013 ◽

Cited By ~ 14

Author(s):

Hidetaka Matsumoto ◽

Joan W. Miller ◽

Demetrios G. Vavvas

Keyword(s):

Retinal Detachment ◽

Sodium Hyaluronate ◽

Subretinal Injection

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Photoreceptor cell death and rescue in retinal detachment and degenerations

Progress in Retinal and Eye Research ◽

10.1016/j.preteyeres.2013.08.001 ◽

2013 ◽

Vol 37 ◽

pp. 114-140 ◽

Cited By ~ 89

Author(s):

Yusuke Murakami ◽

Shoji Notomi ◽

Toshio Hisatomi ◽

Toru Nakazawa ◽

Tatsuro Ishibashi ◽

...

Keyword(s):

Cell Death ◽

Retinal Detachment ◽

Photoreceptor Cell

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Blocking the Necroptosis Pathway Decreases RPE and Photoreceptor Damage Induced by NaIO3

10.1101/387068 ◽

2018 ◽

Cited By ~ 1

Author(s):

Haijiang Lin ◽

Miin Roh ◽

Hidetaka Matsumoto ◽

Alp Atik ◽

Peggy Bouzika ◽

...

Keyword(s):

Cell Death ◽

Photoreceptor Cell ◽

Cell Damage ◽

Outer Nuclear Layer ◽

Cell Loss ◽

Tunel Staining ◽

Programmed Necrosis ◽

Cell Death Pathway ◽

Whole Mount

AbstractPurposeSodium iodate (NaIO3) has been extensively used as a retinotoxin to induce RPE cell damage and degeneration of photoreceptorsin vitroandin vivo. RIP-Kinase dependent programmed necrosis is an important redundant cell death pathway involved in photoreceptor cell death. We wanted to determine whether these pathways are actively involved in RPE and photoreceptor cell death after NaIO3 insult.MethodsARPE-19 cells were exposed to different concentrations of NaIO3 in the presence or absence of various concentrations of a RIPK inhibitor (Nec-1) or a pan-caspase inhibitor (Z-VAD), individually or combined. Cell death was determined at different time points by MTT (Sigma-Aldrich), LDH (Promega) and TUNEL (Millipore) assay. C57BL/6 and RIP3−/-mice were treated with a peritoneal injection of NaIO3 and eyes were enucleated at day 3 or 7. TUNEL staining was used to evaluate photoreceptor cell death. Photoreceptor cell loss was evaluated by measuring the thickness of outer nuclear layer (ONL). Microglia in the ONL were quantified in a retinal whole mount with Iba-1 antibody. RPE degeneration was also assessed in a RPE whole mount, with ZO-1 antibody.ResultsNaIO3 resulted in significant cell death of ARPE-19 cells. Treatment with Nec-1 resulted in better protection than treatment with Z-VAD (P<0.01). A synergistic protective effect was observed when co-treating the cells with Nec-1 and Z-VAD. Nec-1 treatment also decreased the ARPE-19 mitochondrial damage caused by NaIO3.In vivoadministration of NaIO3 resulted in significant RPE and photoreceptor destruction with substantial inflammatory cell infiltration. RIP3 knockout animals displayed considerably less RPE and photoreceptor cell loss, as well as drastically less inflammation.ConclusionsProgrammed necrosis is an important cell death pathway mediating NaIO3 RPE and photoreceptor cell toxicity. Blocking the necroptosis pathway may serve as a novel therapeutic strategy for various RPE degenerative diseases.

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Microglia inhibit photoreceptor cell death and regulate immune cell infiltration in response to retinal detachment

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719601115 ◽

2018 ◽

Vol 115 (27) ◽

pp. E6264-E6273 ◽

Cited By ~ 41

Author(s):

Yoko Okunuki ◽

Ryo Mukai ◽

Elizabeth A. Pearsall ◽

Garrett Klokman ◽

Deeba Husain ◽

...

Keyword(s):

Cell Death ◽

Retinal Detachment ◽

Immune Cells ◽

Photoreceptor Cell ◽

Immune Cell ◽

Photoreceptor Layer ◽

Activated Microglia ◽

Retinal Microglia ◽

Permanent Loss ◽

And Function

Retinal detachment (RD) is a sight-threatening complication common in many highly prevalent retinal disorders. RD rapidly leads to photoreceptor cell death beginning within 12 h following detachment. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common, leading to significant and permanent loss of vision. Microglia are the resident immune cells of the central nervous system, including the retina, and function in the homeostatic maintenance of the neuro-retinal microenvironment. It is known that microglia become activated and change their morphology in retinal diseases. However, the function of activated microglia in RD is incompletely understood, in part because of the lack of microglia-specific markers. Here, using the newly identified microglia marker P2ry12 and microglial depletion strategies, we demonstrate that retinal microglia are rapidly activated in response to RD and migrate into the injured area within 24 h post-RD, where they closely associate with infiltrating macrophages, a population distinct from microglia. Once in the injured photoreceptor layer, activated microglia can be observed to contain autofluorescence within their cell bodies, suggesting they function to phagocytose injured or dying photoreceptors. Depletion of retinal microglia results in increased disease severity and inhibition of macrophage infiltration, suggesting that microglia are involved in regulating neuroinflammation in the retina. Our work identifies that microglia mediate photoreceptor survival in RD and suggests that this effect may be due to microglial regulation of immune cells and photoreceptor phagocytosis.

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