Age-related macular degeneration: A two-level model hypothesis

Rozing, Maarten P.; Durhuus, Jon Ambæk; Nielsen, Marie Krogh; Subhi, Yousif; Kirkwood, Thomas B. L.; Westendorp, Rudi G.J.; Sørensen, Torben Lykke

doi:10.1016/j.preteyeres.2019.100825

Cited by 127 publications

(94 citation statements)

References 314 publications

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“…In our study, we have applied the stimulus on the basal side of the RPE to simulate a systemic inflammation. Our data support the hypothesis that systemic inflammation may contribute to the development of AMD [25,26], as our basal (corresponding to the side of the choroid) pro-inflammatory stimuli induce pro-inflammatory cytokine release in the RPE and a disruption of the RPE barrier function. These results are also supported by a recent in vivo study that showed that a systemic virus infection can alter the expression of chemokines and complement factors in the RPE/choroid [68].…”

Section: Discussionsupporting

confidence: 89%

“…AMD is a multifactorial disease, of which systemic inflammation is discussed as a potentially major contributing factor. Studies show elevated systemic cytokine concentrations and inadequate systemic immune modulation [25][26][27][28][29]. In the retina, the RPE is in close contact with the choroid, and because of its sentinel function, it may react to systemic proinflammatory signals presented at the choroidal (basal) side, which may have consequences for the inflammatory milieu at the retinal (apical) side.…”

Section: Introductionmentioning

confidence: 99%

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Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Terheyden

Roider

Klettner

2020

Graefes Arch Clin Exp Ophthalmol

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Purpose Systemic inflammation may be of importance in the development of AMD. RPE cells can recognize danger signals with toll-like receptors (TLR) and may react in a pro-inflammatory manner. In this study, we evaluated the basal and apical secretions of TNFα, IL-6, and IL-1β in primary RPE cells and RPE/choroid explant cells under basolateral stimulation of TLR2, 3, and 4; the effects on barrier function; and their influence on neuronal cell viability. Methods RPE/choroid tissue explants were prepared from porcine eyes and cultivated in modified Ussing chambers; primary porcine RPE cells on transwell plates. Cells were basally stimulated with agonists Pam2CSK4 (Pam; TLR2), polyinosinic/polycytidylic acid (Poly I:C; TLR3), and lipopolysaccharide (LPS; TLR4) for 24 h. Supernatants were evaluated with ELISA for cytokines TNFα, IL-6, and IL-1β. Apical supernatants were applied to SHSY-5Y cells, and cell viability was evaluated in MTT assay. Barrier function was tested by measuring transepithelial electrical resistance (TER) and occludin immunostaining. Results None of the tested TLR agonists was toxic on RPE cells after 24 h of exposure. Unstimulated RPE cells secreted hardly any cytokines. Pam induced IL-6, IL-1ß, and TNFα on the basal and apical sides at all concentrations tested. Poly I:C induced IL-6 and TNFα primarily at the basal side at lower but on both sides at higher concentrations. LPS induced IL-6, IL-1ß, and TNFα apically and basally at all concentrations tested. In the RPE/choroid, a strong difference between apical and basal secretions could be found. IL-6 was constitutively secreted basally, but not apically, but was induced by all agonists on both sides. IL-1ß and TNFα alpha were strongly induced on the basal side by all agonists. TER was reduced by all agonists, with Pam and LPS being effective in all concentrations tested. Occludin expression was unaltered, but the distribution was influenced by the agonists, with a less distinct localization at the cell borders after treatment. None of the agonists or supernatants of treated RPE and RPE/choroid organ cultures exerted any effect on viability of SHSY-5Y cells. Conclusions Danger signals activating TLRs can induce polarized cytokine expression and contribute to the loss of barrier function in the RPE.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Terheyden

Roider

Klettner

2020

Graefes Arch Clin Exp Ophthalmol

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“…33 With aging, decreased blood flow together with RPE and brunch membrane changes and thickening cause uncontrolled accumulation of cellular debris, making the eye more sensitive to proinflammatory processes. 8 During aging, oxidative damage increases and antioxidant capacity decreases simultaneously, thereby reducing the natural repair capacity of RPE cells. 9 Oxidative Therapeutic Advances in Ophthalmology 12 6 journals.sagepub.com/home/oed damage which increases with aging is associated with diseases such as Parkinson, Alzheimer's, atherosclerosis, and cancer, as well as AMD.…”

Section: Discussionmentioning

confidence: 99%

Serum malondialdehyde, monocyte chemoattractant protein-1, and vitamin C levels in wet type age-related macular degeneration patients

et al. 2020

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Purpose: The purpose of this study was to investigate the serum levels of malondialdehyde (MDA) which is a marker of oxidative stress, monocyte chemoattractant protein-1 (MCP-1) which has an important role in inflammation, and vitamin C which has antioxidant properties in patients with wet age-related macular degeneration (wAMD). Methods: Thirty patients with wAMD were included in the study and serum levels of MDA, MCP-1, and vitamin C were compared with healthy participants ( n = 30). Serum vitamin C and MDA levels were measured using a spectrophotometric method. Serum MCP-1 levels were determined by the ELISA method. Results: MCP-1 and MDA levels were higher in patients with wAMD compared with the control group ( p < 0.05). Serum vitamin C levels were lower in patients with wAMD compared with the control group ( p < 0.05). Conclusions: The increase in the MCP-1 levels in patients with wAMD may be associated with increased inflammation in wAMD. Decreased serum vitamin C and elevated MDA levels in patients with wAMD suggest increased oxidative stress in wAMD patients. These results indicate that the increased oxidative stress and inflammation can play a role in the pathogenesis of wAMD.

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“…Oxidative stress is an important molecular mechanism of AMD (and a primary cause of necroptosis) leading to RPE damage [ 114 ]. In 2016, Hanus et al [ 88 ] for the first time showed the existence of necroptosis in a sodium iodate induced-AMD in vitro model.…”

Section: Novel Pcd Is Associated With Amdmentioning

confidence: 99%

“…As oxidative stress triggers necroptosis, thereby aggravating the development of AMD [ 114 ], targeting necroptosis might be an alternative in addition to suppressing oxidative stress, as cell death is harder to reverse via oxidative stress once it happens. Because of the limited therapeutic options nowadays, future studies should evaluate necroptosis as a potential novel target for AMD.…”

Section: Novel Pcd: New Future Therapeutic Targets For Amd?mentioning

confidence: 99%

Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

Yang

Lam

2020

IJMS

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Age-related macular degeneration (AMD) is a leading cause of severe visual loss among the elderly. AMD patients are tormented by progressive central blurring/loss of vision and have limited therapeutic options to date. Drusen accumulation causing retinal pigment epithelial (RPE) cell damage is the hallmark of AMD pathogenesis, in which oxidative stress and inflammation are the well-known molecular mechanisms. However, the underlying mechanisms of how RPE responds when exposed to drusen are still poorly understood. Programmed cell death (PCD) plays an important role in cellular responses to stress and the regulation of homeostasis and diseases. Apart from the classical apoptosis, recent studies also discovered novel PCD pathways such as pyroptosis, necroptosis, and ferroptosis, which may contribute to RPE cell death in AMD. This evidence may yield new treatment targets for AMD. In this review, we summarized and analyzed recent advances on the association between novel PCD and AMD, proposing PCD’s role as a therapeutic new target for future AMD treatment.

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Age-related macular degeneration: A two-level model hypothesis

Cited by 127 publications

References 314 publications

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Basolateral activation with TLR agonists induces polarized cytokine release and reduces barrier function in RPE in vitro

Serum malondialdehyde, monocyte chemoattractant protein-1, and vitamin C levels in wet type age-related macular degeneration patients

Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

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