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13 pages, 2959 KiB

Open AccessArticle

Early Depletion of Neutrophils Reduces Retinal Inflammation and Neovascularization in Mice with Oxygen-Induced Retinopathy

by Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Xiuying Tang, Abhirup Jayasimhan and Jennifer L. Wilkinson-Berka

Int. J. Mol. Sci. 2023, 24(21), 15680; https://doi.org/10.3390/ijms242115680 - 27 Oct 2023

Cited by 2 | Viewed by 1078

Abstract

Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal [...] Read more.

Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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11 pages, 1719 KiB

Open AccessArticle

Gene Augmentation of CHM Using Non-Viral Episomal Vectors in Models of Choroideremia

by Lyes Toualbi, Maria Toms, Patrick Vingadas Almeida, Richard Harbottle and Mariya Moosajee

Int. J. Mol. Sci. 2023, 24(20), 15225; https://doi.org/10.3390/ijms242015225 - 16 Oct 2023

Cited by 1 | Viewed by 1596

Abstract

Choroideremia (CHM) is an X-linked chorioretinal dystrophy leading to progressive retinal degeneration that results in blindness by late adulthood. It is caused by mutations in the CHM gene encoding the Rab Escort Protein 1 (REP1), which plays a crucial role in the prenylation [...] Read more.

Choroideremia (CHM) is an X-linked chorioretinal dystrophy leading to progressive retinal degeneration that results in blindness by late adulthood. It is caused by mutations in the CHM gene encoding the Rab Escort Protein 1 (REP1), which plays a crucial role in the prenylation of Rab proteins ensuring correct intracellular trafficking. Gene augmentation is a promising therapeutic strategy, and there are several completed and ongoing clinical trials for treating CHM using adeno-associated virus (AAV) vectors. However, late-phase trials have failed to show significant functional improvements and have raised safety concerns about inflammatory events potentially caused by the use of viruses. Therefore, alternative non-viral therapies are desirable. Episomal scaffold/matrix attachment region (S/MAR)-based plasmid vectors were generated containing the human CHM coding sequence, a GFP reporter gene, and ubiquitous promoters (pS/MAR-CHM). The vectors were assessed in two choroideremia disease model systems: (1) CHM patient-derived fibroblasts and (2) chm^ru848 zebrafish, using Western blotting to detect REP1 protein expression and in vitro prenylation assays to assess the rescue of prenylation function. Retinal immunohistochemistry was used to investigate vector expression and photoreceptor morphology in injected zebrafish retinas. The pS/MAR-CHM vectors generated persistent REP1 expression in CHM patient fibroblasts and showed a significant rescue of prenylation function by 75%, indicating correction of the underlying biochemical defect associated with CHM. In addition, GFP and human REP1 expression were detected in zebrafish microinjected with the pS/MAR-CHM at the one-cell stage. Injected chm^ru848 zebrafish showed increased survival, prenylation function, and improved retinal photoreceptor morphology. Non-viral S/MAR vectors show promise as a potential gene-augmentation strategy without the use of immunogenic viral components, which could be applicable to many inherited retinal disease genes. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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13 pages, 2222 KiB

Open AccessCommunication

Proteomics Analysis of R-Ras Deficiency in Oxygen Induced Retinopathy

by Maria Vähätupa, Janika Nättinen, Ulla Aapola, Hannele Uusitalo-Järvinen, Hannu Uusitalo and Tero A. H. Järvinen

Int. J. Mol. Sci. 2023, 24(9), 7914; https://doi.org/10.3390/ijms24097914 - 26 Apr 2023

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Abstract

Small GTPase R-Ras regulates vascular permeability in angiogenesis. In the eye, abnormal angiogenesis and hyperpermeability are the leading causes of vision loss in several ischemic retinal diseases such as proliferative diabetic retinopathy (PDR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). Oxygen-induced [...] Read more.

Small GTPase R-Ras regulates vascular permeability in angiogenesis. In the eye, abnormal angiogenesis and hyperpermeability are the leading causes of vision loss in several ischemic retinal diseases such as proliferative diabetic retinopathy (PDR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP). Oxygen-induced retinopathy (OIR) is the most widely used experimental model for these ischemic retinopathies. To shed more light on how the R-Ras regulates vascular permeability in pathological angiogenesis, we performed a comprehensive (>2900 proteins) characterization of OIR in R-Ras knockout (KO) and wild-type (WT) mice by sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics. OIR and age-matched normoxic control retinas were collected at P13, P17, and P42 from R-Ras KO and WT mice and were subjected to SWATH-MS and data analysis. The most significant difference between the R-Ras KO and WT retinas was an accumulation of plasma proteins. The pathological vascular hyperpermeability during OIR in the R-Ras KO retina took place very early, P13. This led to simultaneous hypoxic cell injury/death (ferroptosis), glycolytic metabolism as well compensatory mechanisms to counter the pathological leakage from angiogenic blood vessels in the OIR retina of R-Ras deficient mice. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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11 pages, 1921 KiB

Open AccessArticle

IL-17A Enhances Retinal Neovascularization

by Brooklyn E. Taylor, Chieh A. Lee, Thomas E. Zapadka, Amy Y. Zhou, Katherine G. Barber, Zakary R. R. Taylor, Scott J. Howell and Patricia R. Taylor

Int. J. Mol. Sci. 2023, 24(2), 1747; https://doi.org/10.3390/ijms24021747 - 16 Jan 2023

Cited by 2 | Viewed by 1703

Abstract

Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays [...] Read more.

Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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11 pages, 2608 KiB

Open AccessArticle

Higher Circulating Levels of Neutrophils and Basophils Are Linked to Myopic Retinopathy

by Jinyan Qi, Wei Pan, Ting Peng, Ling Zeng, Xiaoning Li, Zhongping Chen, Zhikuan Yang and Heping Xu

Int. J. Mol. Sci. 2023, 24(1), 80; https://doi.org/10.3390/ijms24010080 - 21 Dec 2022

Cited by 4 | Viewed by 1854

Abstract

This retrospective study investigated circulating immune cell alteration in patients with myopic retinopathy. Blood test results and demographic and ocular information of 392 myopic patients and 129 emmetropia controls who attended Changsha Aier Eye Hospital from May 2017 to April 2022 were used [...] Read more.

This retrospective study investigated circulating immune cell alteration in patients with myopic retinopathy. Blood test results and demographic and ocular information of 392 myopic patients and 129 emmetropia controls who attended Changsha Aier Eye Hospital from May 2017 to April 2022 were used in this study. Compared with emmetropia, the percentages of neutrophils and basophils and neutrophil/lymphocyte ratio were significantly higher in myopic patients, whereas the percentages of monocytes and lymphocytes and the counts of lymphocytes and eosinophils were significantly lower in myopic patients. After adjusting for age and hypertension/diabetes, the difference remained. Interestingly, the platelet counts were significantly lower in myopic patients after the adjustments. Further subgroup analysis using multivariable linear regression showed that higher levels of neutrophils, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio, lower levels of monocytes, eosinophils, lymphocytes, and platelets, were related to myopic peripheral retinal degeneration (mPRD) and posterior staphyloma (PS). A higher level of basophils was linked to myopic choroidal neovascularization (mCNV). Our results suggest that higher levels of circulating neutrophils and neutrophil/lymphocyte ratio, lower monocytes, eosinophils, lymphocytes, and platelets are related to mild myopic retinopathy. A higher level of circulating basophils is related to the severe form of myopic retinopathy, such as mCNV. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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Review

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23 pages, 1305 KiB

Open AccessReview

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

by João Gabriel Santos Rosa, Geonildo Rodrigo Disner, Felipe Justiniano Pinto, Carla Lima and Monica Lopes-Ferreira

Int. J. Mol. Sci. 2023, 24(17), 13079; https://doi.org/10.3390/ijms241713079 - 23 Aug 2023

Viewed by 3032

Abstract

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are [...] Read more.

Visual impairment and blindness are a growing public health problem as they reduce the life quality of millions of people. The management and treatment of these diseases represent scientific and therapeutic challenges because different cellular and molecular actors involved in the pathophysiology are still being identified. Visual system components, particularly retinal cells, are extremely sensitive to genetic or metabolic alterations, and immune responses activated by local insults contribute to biological events, culminating in vision loss and irreversible blindness. Several ocular diseases are linked to retinal cell loss, and some of them, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and diabetic retinopathy, are characterized by pathophysiological hallmarks that represent possibilities to study and develop novel treatments for retinal cell degeneration. Here, we present a compilation of revisited information on retinal degeneration, including pathophysiological and molecular features and biochemical hallmarks, and possible research directions for novel treatments to assist as a guide for innovative research. The knowledge expansion upon the mechanistic bases of the pathobiology of eye diseases, including information on complex interactions of genetic predisposition, chronic inflammation, and environmental and aging-related factors, will prompt the identification of new therapeutic strategies. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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17 pages, 977 KiB

Open AccessReview

Blue Light—Ocular and Systemic Damaging Effects: A Narrative Review

by Răzvan-Geo Antemie, Ovidiu Ciprian Samoilă and Simona Valeria Clichici

Int. J. Mol. Sci. 2023, 24(6), 5998; https://doi.org/10.3390/ijms24065998 - 22 Mar 2023

Cited by 1 | Viewed by 3323

Abstract

Light is a fundamental aspect of our lives, being involved in the regulation of numerous processes in our body. While blue light has always existed in nature, with the ever-growing number of electronic devices that make use of short wavelength (blue) light, the [...] Read more.

Light is a fundamental aspect of our lives, being involved in the regulation of numerous processes in our body. While blue light has always existed in nature, with the ever-growing number of electronic devices that make use of short wavelength (blue) light, the human retina has seen increased exposure to it. Because it is at the high-energy end of the visible spectrum, many authors have investigated the theoretical harmful effects that it poses to the human retina and, more recently, the human body, given the discovery and characterization of the intrinsically photosensitive retinal ganglion cells. Many approaches have been explored, with the focus shifting throughout the years from examining classic ophthalmological parameters, such as visual acuity, and contrast sensitivity to more complex ones seen on electrophysiological assays and optical coherence tomographies. The current study aims to gather the most recent relevant data, reveal encountered pitfalls, and suggest future directions for studies regarding local and/or systemic effects of blue light retinal exposures. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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21 pages, 703 KiB

Open AccessReview

An Overview towards Zebrafish Larvae as a Model for Ocular Diseases

by João Gabriel Santos Rosa, Monica Lopes-Ferreira and Carla Lima

Int. J. Mol. Sci. 2023, 24(6), 5387; https://doi.org/10.3390/ijms24065387 - 11 Mar 2023

Cited by 1 | Viewed by 2697

Abstract

Despite the obvious morphological differences in the visual system, zebrafish share a similar architecture and components of the same embryonic origin as humans. The zebrafish retina has the same layered structure and cell types with similar metabolic and phototransduction support as humans, and [...] Read more.

Despite the obvious morphological differences in the visual system, zebrafish share a similar architecture and components of the same embryonic origin as humans. The zebrafish retina has the same layered structure and cell types with similar metabolic and phototransduction support as humans, and is functional 72 h after fertilization, allowing tests of visual function to be performed. The zebrafish genomic database supports genetic mapping studies as well as gene editing, both of which are useful in the ophthalmological field. It is possible to model ocular disorders in zebrafish, as well as inherited retinal diseases or congenital or acquired malformations. Several approaches allow the evaluation of local pathological processes derived from systemic disorders, such as chemical exposure to produce retinal hypoxia or glucose exposure to produce hyperglycemia, mimicking retinopathy of prematurity or diabetic retinopathy, respectively. The pathogenesis of ocular infections, autoimmune diseases, or aging can also be assessed in zebrafish larvae, and the preserved cellular and molecular immune mechanisms can be assessed. Finally, the zebrafish model for the study of the pathologies of the visual system complements certain deficiencies in experimental models of mammals since the regeneration of the zebrafish retina is a valuable tool for the study of degenerative processes and the discovery of new drugs and therapies. Full article

(This article belongs to the Special Issue Novel Insights in Retinal Diseases Pathophysiology and Therapies 2.0)

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