The Role of Inflammation in AMD (Multifactorial Age-Related Macular Degeneration)

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (20 April 2023) | Viewed by 23184

Special Issue Editors


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Guest Editor
1. Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland
2. Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
Interests: autophagy; oxidative stress; inflammation; lysosome; retinal pigment epithelium; reactive oxygen species; lipid peroxidation; age-related macular degeneration
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Guest Editor
Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, 70210 Kuopio, Finland
Interests: inflammation; allergens; HLA; retinal pigment epithelium; oxidative stress; T lymphocytes; signaling pathways
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK
Interests: retinal immune regulation; inflammation; aging; retinal degeneration; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The most common reason for blindness in developed countries is multifactorial age-related macular degeneration (AMD). Its development is associated with aging, gene defects, hypercholesterolemia, hypertension, arteriosclerosis, obesity, smoking, and unhealthy diet. AMD patients have problems in daily routines, such as reading, watching TV, driving, and recognizing faces. Straight lines appear wavy or crooked, objects look smaller than normal, and colors are less bright. At the tissue and cellular levels, rod and cone photoreceptors, retinal pigment epithelial cells, and the underlying choroid perform metabolic alterations and degenerative changes in AMD. Chronic oxidative stress, impaired autophagy, mitochondrial dysfunction, and inflammation are strongly linked to AMD.

Reactive oxygen species and oxidized molecules are considered to be major causes of cellular stress resulting in innate immunity responses through the activation of cell-associated and soluble pattern recognition receptors (PRRs), such as Toll-like or NOD-like receptors (TLR or NLRs), complement factors, scavenger receptors, or pentraxins in AMD pathology. Eventually, chronic oxidative stress, inflammation, and paracellular permeability changes may induce outer blood retinal barrier dysfunction and promote cellular phenotype changes, finally leading to late-state AMD and visual loss.

In this Special Issue of the journal Cells, we would like to invite you to provide original clinical reports, experimental studies utilizing cell and animal models, and reviews or shorter perspective articles on all aspects related to the theme of “The Role of Inflammation in AMD”. Expert articles describing genetics/epigenetics, metabolic, mechanistic, functional, cellular, biochemical, or general aspects of inflammation in AMD are warmly welcome.

Prof. Dr. Kai Kaarniranta
Prof. Dr. Anu Kauppinen
Prof. Dr. Heping Xu
Guest Editor

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Keywords

  • aging
  • autophagy
  • degeneration
  • inflammation
  • macula
  • oxidative stress
  • retina

Related Special Issue

Published Papers (9 papers)

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Research

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24 pages, 3216 KiB  
Article
Red Wine Extract Prevents Oxidative Stress and Inflammation in ARPE-19 Retinal Cells
by Clarisse Cornebise, Maude Perus, François Hermetet, Josep Valls-Fonayet, Tristan Richard, Virginie Aires and Dominique Delmas
Cells 2023, 12(10), 1408; https://doi.org/10.3390/cells12101408 - 17 May 2023
Cited by 1 | Viewed by 1794
Abstract
Age-related macular degeneration (AMD) is one of the most commonly occurring ocular diseases worldwide. This degenerative condition affects the retina and leads to the loss of central vision. The current treatments are focused on the late stage of the disease, but recent studies [...] Read more.
Age-related macular degeneration (AMD) is one of the most commonly occurring ocular diseases worldwide. This degenerative condition affects the retina and leads to the loss of central vision. The current treatments are focused on the late stage of the disease, but recent studies have highlighted the importance and benefits of preventive treatments and how good dietary habits can reduce the risk of progression to an advanced form of the disease. In this context, we studied whether resveratrol (RSV) or a polyphenolic cocktail, red wine extract (RWE), are able to prevent the initiating events of AMD (i.e., oxidative stress and inflammation) in human ARPE-19 retinal pigment epithelial (RPE) cells and macrophages. This study highlights that RWE and RSV can prevent hydrogen peroxide (H2O2) or 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH)-induced oxidative stress and can subsequently prevent DNA damage via the inhibition of the ATM (ataxia telangiectasia-mutated)/Chk2 (checkpoint kinase 2) or Chk1 signaling pathways, respectively. Moreover, ELISA assays show that RWE and RSV can prevent the secretion of proinflammatory cytokines in RPE cells and in human macrophages. Interestingly, RWE exhibits a greater protective impact compared to RSV alone, even though RSV was more concentrated when used alone than in the red wine extract. Our results suggest that RWE and RSV may have potential interest as preventive nutritional supplementations against AMD. Full article
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17 pages, 2743 KiB  
Article
Analysis of Wild Type and Variant B Cystatin C Interactome in Retinal Pigment Epithelium Cells Reveals Variant B Interacting Mitochondrial Proteins
by Emil Carlsson, Umar Sharif, Wasu Supharattanasitthi and Luminita Paraoan
Cells 2023, 12(5), 713; https://doi.org/10.3390/cells12050713 - 23 Feb 2023
Viewed by 1933
Abstract
Cystatin C, a secreted cysteine protease inhibitor, is abundantly expressed in retinal pigment epithelium (RPE) cells. A mutation in the protein’s leader sequence, corresponding to formation of an alternate variant B protein, has been linked with an increased risk for both age-related macular [...] Read more.
Cystatin C, a secreted cysteine protease inhibitor, is abundantly expressed in retinal pigment epithelium (RPE) cells. A mutation in the protein’s leader sequence, corresponding to formation of an alternate variant B protein, has been linked with an increased risk for both age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Variant B cystatin C displays intracellular mistrafficking with partial mitochondrial association. We hypothesized that variant B cystatin C interacts with mitochondrial proteins and impacts mitochondrial function. We sought to determine how the interactome of the disease-related variant B cystatin C differs from that of the wild-type (WT) form. For this purpose, we expressed cystatin C Halo-tag fusion constructs in RPE cells to pull down proteins interacting with either the WT or variant B form, followed by identification and quantification by mass spectrometry. We identified a total of 28 interacting proteins, of which 8 were exclusively pulled down by variant B cystatin C. These included 18 kDa translocator protein (TSPO) and cytochrome B5 type B, both of which are localized to the mitochondrial outer membrane. Variant B cystatin C expression also affected RPE mitochondrial function with increased membrane potential and susceptibility to damage-induced ROS production. The findings help us to understand how variant B cystatin C differs functionally from the WT form and provide leads to RPE processes adversely affected by the variant B genotype. Full article
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17 pages, 7812 KiB  
Article
Oxidative Stress and Lipid Accumulation Augments Cell Death in LDLR-Deficient RPE Cells and Ldlr−/− Mice
by Parameswaran Gangadharan Sreekumar, Feng Su, Christine Spee, Eduardo Araujo, Steven Nusinowitz, Srinivasa T Reddy and Ram Kannan
Cells 2023, 12(1), 43; https://doi.org/10.3390/cells12010043 - 22 Dec 2022
Cited by 7 | Viewed by 2034
Abstract
Lipid peroxidation from oxidative stress is considered a major contributor to age-related macular degeneration (AMD). The retina is abundant with circulating low-density lipoproteins (LDL), which are taken up by LDL receptor (LDLR) in the RPE and Müller cells. The purpose of this study [...] Read more.
Lipid peroxidation from oxidative stress is considered a major contributor to age-related macular degeneration (AMD). The retina is abundant with circulating low-density lipoproteins (LDL), which are taken up by LDL receptor (LDLR) in the RPE and Müller cells. The purpose of this study is to investigate the role of LDLR in the NaIO3-induced model of dry AMD. Confluent primary human RPE (hRPE) and LDLR-silenced ARPE-19 cells were stressed with 150 µM tert-butyl hydroperoxide (tBH) and caspase 3/7 activation was determined. WT and Ldlr−/− mice were administered NaIO3 (20 mg/kg) intravenously. On day 7, fundus imaging, OCT, ERG, and retinal thickness were measured. Histology, TUNEL, cleaved caspase 3 and lipid accumulation were assessed. Treatment of hRPE with tBH markedly decreased LDLR expression. Caspase 3/7 activation was significantly increased in LDLR-silenced ARPE-19 cells treated with tBH. In Ldlr−/− mice, NaIO3 administration resulted in significant (a) retinal thinning, (b) compromised photoreceptor function, (c) increased percentage of cleaved caspase 3 positive and apoptotic cells, and (d) increased lipid droplet accumulation in the RPE, Bruch membrane, choroid, and sclera, compared to WT mice. Our findings imply that LDLR loss leads to lipid accumulation and impaired retinal function, which may contribute to the development of AMD. Full article
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19 pages, 7244 KiB  
Article
Microglia–Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model
by Maeve Boyce, Ying Xin, Olivia Chowdhury, Peng Shang, Haitao Liu, Victoria Koontz, Anastasia Strizhakova, Mihir Nemani, Stacey Hose, J. Samuel Zigler, Jr., Matthew Campbell, Debasish Sinha, James T. Handa, Kai Kaarniranta, Jiang Qian and Sayan Ghosh
Cells 2022, 11(22), 3535; https://doi.org/10.3390/cells11223535 - 9 Nov 2022
Cited by 9 | Viewed by 2681
Abstract
In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how [...] Read more.
In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how these cells interact with each other in AMD. Here, we report a novel concept of how dynamic interactions between microglia and neutrophils contribute to AMD pathology. Using well-characterized genetically engineered mouse models as tools, we show that in the diseased state, retinal pigmented epithelial (RPE) cells trigger pro-inflammatory (M1) transition in microglia with diminished expression of the homeostatic marker, CX3CR1. Activated microglia localize to the SRS and regulate local neutrophil function, triggering their activation and thereby inducing early RPE changes. Ligand receptor (LR)-loop analysis and cell culture studies revealed that M1 microglia also induce the expression of neutrophil adhesion mediators (integrin β1/α4) through their interaction with CD14 on microglia. Furthermore, microglia-induced neutrophil activation and subsequent neutrophil-mediated RPE alterations were mitigated by inhibiting Akt2 in microglia. These results suggest that the Akt2 pathway in microglia drives M1 microglia-mediated neutrophil activation, thereby triggering early RPE degeneration and is a novel therapeutic target for early AMD, a stage without treatment options. Full article
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18 pages, 2622 KiB  
Article
Inflammasome Activation in Retinal Pigment Epithelium from Human Donors with Age-Related Macular Degeneration
by Mara C. Ebeling, Cody R. Fisher, Rebecca J. Kapphahn, Madilyn R. Stahl, Shichen Shen, Jun Qu, Sandra R. Montezuma and Deborah A. Ferrington
Cells 2022, 11(13), 2075; https://doi.org/10.3390/cells11132075 - 30 Jun 2022
Cited by 6 | Viewed by 2274
Abstract
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. One of the risk factors associated with developing AMD is the single nucleotide polymorphism (SNP) found within the gene [...] Read more.
Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. One of the risk factors associated with developing AMD is the single nucleotide polymorphism (SNP) found within the gene encoding complement factor H (CFH). Part of the innate immune system, CFH inhibits alternative complement pathway activation. Multi-protein complexes called inflammasomes also play a role in the innate immune response. Previous studies reported that inflammasome activation may contribute to AMD pathology. In this study, we used primary human adult RPE cell cultures from multiple donors, with and without AMD, that were genotyped for the Y402H CFH risk allele. We found complement and inflammasome-related genes and proteins at basal levels in RPE tissue and cell cultures. Additionally, treatment with rotenone, bafilomycin A, and ATP led to inflammasome activation. Overall, the response to priming and activation was similar, irrespective of disease state or CFH genotype. While these data show that the inflammasome is present and active in RPE, our results suggest that inflammasome activation may not contribute to early AMD pathology. Full article
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Review

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17 pages, 1938 KiB  
Review
The Role of Inflammation in Age-Related Macular Degeneration—Therapeutic Landscapes in Geographic Atrophy
by Grace A. Borchert, Hoda Shamsnajafabadi, Monica L. Hu, Samantha R. De Silva, Susan M. Downes, Robert E. MacLaren, Kanmin Xue and Jasmina Cehajic-Kapetanovic
Cells 2023, 12(16), 2092; https://doi.org/10.3390/cells12162092 - 18 Aug 2023
Cited by 6 | Viewed by 2441
Abstract
Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy. Full article
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25 pages, 460 KiB  
Review
Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment
by Adnan H. Khan, Itay Chowers and Andrew J. Lotery
Cells 2023, 12(13), 1708; https://doi.org/10.3390/cells12131708 - 23 Jun 2023
Cited by 4 | Viewed by 1879
Abstract
Landmark genetic studies have revealed the effect of complement biology and its regulation on the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at [...] Read more.
Landmark genetic studies have revealed the effect of complement biology and its regulation on the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at play. Substantial evidence supports the role of para-inflammation in maintaining homeostasis in the retina and choroid. With increasing age, a decline in immune system regulation, known as immunosenescence, has been shown to alter the equilibrium maintained by para-inflammation. The altered equilibrium results in chronic, sterile inflammation with aging, termed ‘inflammaging’, including in the retina and choroid. The chronic inflammatory state in AMD is complex, with contributions from cells of the innate and adaptive branches of the immune system, sometimes with overlapping features, and the interaction of their secretory products with retinal cells such as microglia and retinal pigment epithelium (RPE), extracellular matrix and choroidal vascular endothelial cells. In this review, the chronic inflammatory state in AMD will be explored by immune cell type, with a discussion of factors that will need to be overcome in the development of curative therapies. Full article
19 pages, 905 KiB  
Review
The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies
by Federico Manai, Stefano Govoni and Marialaura Amadio
Cells 2022, 11(24), 4061; https://doi.org/10.3390/cells11244061 - 15 Dec 2022
Cited by 5 | Viewed by 2437
Abstract
Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is [...] Read more.
Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF’s mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene–disease (KEAP1-AMD) database search, followed by a protein–protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts. Full article
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19 pages, 1416 KiB  
Review
A Linkage between Angiogenesis and Inflammation in Neovascular Age-Related Macular Degeneration
by Hanna Heloterä and Kai Kaarniranta
Cells 2022, 11(21), 3453; https://doi.org/10.3390/cells11213453 - 1 Nov 2022
Cited by 22 | Viewed by 4152
Abstract
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with a limited understanding of its pathogenesis and the number of patients are all the time increasing. AMD is classified into two main forms: dry and neovascular AMD (nAMD). Dry AMD is the most prevalent form (80–90%) of AMD cases. Neovascular AMD (10–20% of AMD cases) is treated with monthly or more sparsely given intravitreal anti-vascular endothelial growth factor inhibitors, but unfortunately, not all patients respond to the current treatments. A clinical hallmark of nAMD is choroidal neovascularization. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Cellular damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to advanced geographic atrophy and/or choroidal neovascularization and fibrosis. Currently, it is not fully known why different AMD phenotypes develop. In this review, we connect angiogenesis and inflammatory regulators in the development of nAMD and discuss therapy challenges and hopes. Full article
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