Subretinal fibrosis in neovascular age-related macular degeneration: current concepts, therapeutic avenues, and future perspectives

AbstractAge-related macular degeneration (AMD) is a progressive, degenerative disease of the human retina which in its most aggressive form is associated with the formation of macular neovascularization (MNV) and subretinal fibrosis leading to irreversible blindness. MNVs contain blood vessels as well as infiltrating immune cells, myofibroblasts, and excessive amounts of extracellular matrix proteins such as collagens, fibronectin, and laminin which disrupts retinal function and triggers neurodegeneration. In the mammalian retina, damaged neurons cannot be replaced by tissue regeneration, and subretinal MNV and fibrosis persist and thus fuel degeneration and visual loss. This review provides an overview of subretinal fibrosis in neovascular AMD, by summarizing its clinical manifestations, exploring the current understanding of the underlying cellular and molecular mechanisms and discussing potential therapeutic approaches to inhibit subretinal fibrosis in the future.

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Molecular mechanisms of subretinal fibrosis in age-related macular degeneration

Experimental Eye Research ◽

10.1016/j.exer.2015.03.009 ◽

2016 ◽

Vol 142 ◽

pp. 19-25 ◽

Cited By ~ 67

Author(s):

Keijiro Ishikawa ◽

Ram Kannan ◽

David R. Hinton

Keyword(s):

Macular Degeneration ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Age Related ◽

Subretinal Fibrosis

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Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

Current Molecular Medicine ◽

10.2174/1566524019666190828150625 ◽

2019 ◽

Vol 19 (10) ◽

pp. 705-718 ◽

Cited By ~ 4

Author(s):

Naima Mansoor ◽

Fazli Wahid ◽

Maleeha Azam ◽

Khadim Shah ◽

Anneke I. den Hollander ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Macular Degeneration ◽

Complement System ◽

Molecular Mechanisms ◽

Critical Role ◽

Age Related Macular Degeneration ◽

Genetic Changes ◽

Complement System Proteins ◽

Age Related ◽

Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

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Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration

Journal of Neuroinflammation ◽

10.1186/s12974-020-02033-7 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Karis Little ◽

Maria Llorián-Salvador ◽

Miao Tang ◽

Xuan Du ◽

Stephen Marry ◽

...

Keyword(s):

Growth Factor ◽

Macular Degeneration ◽

Transforming Growth Factor ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Two Stage ◽

Blocking Antibody ◽

Age Related ◽

Subretinal Fibrosis ◽

Isolectin B4

Abstract Background Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. Methods Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. Results Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. Conclusions MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Graphical abstract Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch’s membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.

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Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7901270 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19 ◽

Cited By ~ 9

Author(s):

Samuel Abokyi ◽

Chi-Ho To ◽

Tim T. Lam ◽

Dennis Y. Tse

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Macular Degeneration ◽

Molecular Mechanisms ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Related Factor ◽

Vascular Endothelial ◽

Age Related ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

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Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration

Acta Ophthalmologica ◽

10.1111/j.1755-3768.2011.02179.x ◽

2011 ◽

Vol 90 (4) ◽

pp. 299-309 ◽

Cited By ~ 120

Author(s):

Kati Kinnunen ◽

Goran Petrovski ◽

Morten C. Moe ◽

András Berta ◽

Kai Kaarniranta

Keyword(s):

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Molecular Mechanisms ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Age Related

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Discovery of Novel Genetic Risk Loci for Acute Central Serous Chorioretinopathy and Genetic Pleiotropic Effect With Age-Related Macular Degeneration

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.696885 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lei Feng ◽

Si Chen ◽

Huatuo Dai ◽

Rajkumar Dorajoo ◽

Jianjun Liu ◽

...

Keyword(s):

Macular Degeneration ◽

Genetic Risk ◽

Central Serous Chorioretinopathy ◽

Clinical Manifestations ◽

Pleiotropic Effect ◽

Age Related Macular Degeneration ◽

Chromosome 15 ◽

Nucleotide Polymorphisms ◽

Risk Effects ◽

Age Related

BackgroundCentral serous chorioretinopathy (CSC) is a severe and heterogeneous chorioretinal disorder. Shared clinical manifestations between CSC and age-related macular degeneration (AMD) and the confirmation of CFH as genetic risk locus for both CSC and AMD suggest possible common pathophysiologic mechanisms between two diseases.MethodsTo advance the understanding of genetic susceptibility of CSC and further investigate genetic pleiotropy between CSC and AMD, we performed genetic association analysis of 38 AMD-associated single nucleotide polymorphisms (SNPs) in a Chinese CSC cohort, consisting of 464 patients and 548 matched healthy controls.ResultsTwelve SNPs were found to be associated with CSC at nominal significance (p < 0.05), and four SNPs on chromosomes 1, 4, and 15 showed strong associations whose evidences surpassed Bonferroni (BF)-corrected significance [rs1410996, odds ratios (OR) = 1.47, p = 2.37 × 10–5; rs1329428, OR = 1.40, p = 3.32 × 10–4; rs4698775, OR = 1.45, p = 2.20 × 10–4; and rs2043085, OR = 1.44, p = 1.91 × 10–4]. While the genetic risk effects of rs1410996 and rs1329428 (within the well-established locus CFH) are correlated (due to high LD), rs4698775 on chromosome 4 and rs2043085 on chromosome 15 are novel risk loci for CSC. Polygenetic risk score (PRS) constructed by using three independent SNPs (rs1410996, rs4698775, and rs2043085) showed highly significant association with CSC (p = 2.10 × 10–7), with the top 10% of subjects with high PRS showing 6.39 times higher risk than the bottom 10% of subjects with lowest PRS. Three SNPs were also found to be associated with clinic manifestations of CSC patients. In addition, by comparing the genetic effects (ORs) of these 38 SNPs between CSC and AMD, our study revealed significant, but complex genetic pleiotropic effect between the two diseases.ConclusionBy discovering two novel genetic risk loci and revealing significant genetic pleiotropic effect between CSC and AMD, the current study has provided novel insights into the role of genetic composition in the pathogenesis of CSC.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21197279 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7279 ◽

Cited By ~ 1

Author(s):

Ming Yang ◽

Kwok-Fai So ◽

Wai Ching Lam ◽

Amy Cheuk Yin Lo

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Macular Degeneration ◽

Molecular Mechanisms ◽

Cell Damage ◽

Retinal Pigment ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Severe Visual Loss ◽

Age Related

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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