Triamcinolone regulated apopto-phagocytic gene expression patterns in the clearance of dying retinal pigment epithelial cells. A key role of Mertk in the enhanced phagocytosis

Albert, Réka; Kristóf, Endre; Zahuczky, Gábor; Szatmári-Tóth, Mária; Veréb, Zoltán; Oláh, Brigitta; Moe, Morten C.; Facskó, Andrea; Fésüs, László; Petrovski, Goran

doi:10.1016/j.bbagen.2014.10.026

Cited by 8 publications

(17 citation statements)

References 44 publications

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“… 33 , 70 In a recent study, we showed that MerTk has a key role in the regulation of TC-enhanced phagocytosis of RPE cells by non-professional and professional phagocytes. 41 Here, we demonstrate that autophagy-associated dying RPE cells can be efficiently and increasingly engulfed by macrophages and DCs over time in vitro.…”

Section: Discussionmentioning

confidence: 70%

“…Although phagocytosis of apoptotic-, autophagy-associated dying and necrotic cells has been extensively studied in other organ systems, and we have previously shown the clearance dynamics of apoptotic/anoikic RPE cells in vitro, 41 no data exist on how autophagy-associated dying cells get removed from the retina. Living RPE cells, macrophages and DCs could engulf autophagy-associated dying RPE cells with increasing number of phagocytes containing cell corpses over a 24h period quantified by flow cytometry ( Figures 4a–d and Supplementary Figure 1 ) and demonstrated by time-lapse microscopy ( Supplementary Videos 1 and 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Human macrophages were obtained through a 5-day differentiation using 5 ng/ml macrophage colony-stimulating factor (MCSF) (Peprotech EC, London, Great Britain) at 37 °C in Iscove's Modified Dulbecco's Medium (IMDM) (Gibco) containing 10% human AB serum (Sigma-Aldrich) and 10000 U/ml penicillin and 10 mg/ml streptomycin (Sigma-Aldrich). 41 To differentiate iDCs, monocytes were plated into 6-well culture dishes at a density of 2 × 10 6 cells/ml and cultured for 5 days in serum-free AIM V medium (Gibco) containing 80 ng/ml GMCSF (Peprotech EC) and 100 ng/ml IL-4 (Peprotech EC). On day 2, the same amounts of GMCSF and IL-4 were added to the cell cultures without changing their media for another 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…Phagocytes were pre-treated with 1 μ M TC 48 h prior to the assay. 33 , 41 Dying RPE cells were fed to engulfing cells following the induction of autophagy-associated cell death by 1 mM H 2 O 2 treatment for 2 h. Engulfing cells were stained for 16 h with 7.5 μ M CMTMR, while the dying cells were labeled for 2 h with 12.5 μ M CFDA-SE followed by washing twice with PBS before phagocytosis. Phagocytes and dying RPE cells were mixed at a ratio of 1 : 3 in the absence of human 10% AB serum and incubated for 4, 8, 12 or 24 h at 37 °C, 5% CO 2 atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…The engulfment of these cells by professional or non-professional phagocytes, human macrophages, DCs or RPEs, respectively, was studied accordingly. Furthermore, the effect of TC, a glucocorticoid which we recently described to enhance phagocytosis of anoikic dying RPEs, 41 was studied upon engulfment of autophagy-associated dying RPEs. We show here that autophagy-associated dying RPEs are engulfed by macrophages, DCs and RPE cells in an increasing and time-dependent manner.…”

mentioning

confidence: 99%

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Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

et al. 2016

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Retinal pigment epithelial (RPE) cells can undergo different forms of cell death, including autophagy-associated cell death during age-related macular degeneration (AMD). Failure of macrophages or dendritic cells (DCs) to engulf the different dying cells in the retina may result in the accumulation of debris and progression of AMD. ARPE-19 and primary human RPE cells undergo autophagy-associated cell death upon serum depletion and oxidative stress induced by hydrogen peroxide (H2O2). Autophagy was revealed by elevated light-chain-3 II (LC3-II) expression and electron microscopy, while autophagic flux was confirmed by blocking the autophago-lysosomal fusion using chloroquine (CQ) in these cells. The autophagy-associated dying RPE cells were engulfed by human macrophages, DCs and living RPE cells in an increasing and time-dependent manner. Inhibition of autophagy by 3-methyladenine (3-MA) decreased the engulfment of the autophagy-associated dying cells by macrophages, whereas sorting out the GFP-LC3-positive/autophagic cell population or treatment by the glucocorticoid triamcinolone (TC) enhanced it. Increased amounts of IL-6 and IL-8 were released when autophagy-associated dying RPEs were engulfed by macrophages. Our data suggest that cells undergoing autophagy-associated cell death engage in clearance mechanisms guided by professional and non-professional phagocytes, which is accompanied by inflammation as part of an in vitro modeling of AMD pathogenesis.

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Section: Discussionmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

et al. 2016

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The retinal pigment epithelium

Nagymihály

Nemesh

Ardan

et al. 2021

Tissue Barriers in Disease, Injury and Regeneration

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CB2 receptor activation causes an ERK1/2-dependent inflammatory response in human RPE cells

Hytti

Andjelić

Josifovska

et al. 2017

Sci Rep

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A chronic low-level inflammation contributes to the pathogenesis of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in Western countries. The loss of central vision results from attenuated maintenance of photoreceptors due to the degeneration of retinal pigment epithelium (RPE) cells beneath the photoreceptor layer. It has been proposed that pathologic inflammation initiated in RPE cells could be regulated by the activation of type 2 cannabinoid receptors (CB2). Here, we have analysed the effect of CB2 activation on cellular survival and inflammation in human RPE cells. RPE cells were treated with the selective CB2 agonist JWH-133 in the presence or absence of the oxidative stressor 4-hydroxynonenal. Thereafter, cellular viability as well as the release of pro-inflammatory cytokines and potential underlying signalling pathways were analysed. Our results show that JWH-133 led to increased intracellular Ca2+ levels, suggesting that RPE cells are capable of responding to a CB2 agonist. JWH-133 could not prevent oxidative stress-induced cell death. Instead, 10 µM JWH-133 increased cell death and the release of proinflammatory cytokines in an ERK1/2-dependent manner. In contrast to previous findings, CB2 activation increased, rather than reduced inflammation in RPE cells.

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Triamcinolone regulated apopto-phagocytic gene expression patterns in the clearance of dying retinal pigment epithelial cells. A key role of Mertk in the enhanced phagocytosis

Cited by 8 publications

References 44 publications

Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

Clearance of autophagy-associated dying retinal pigment epithelial cells – a possible source for inflammation in age-related macular degeneration

The retinal pigment epithelium

CB2 receptor activation causes an ERK1/2-dependent inflammatory response in human RPE cells

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