Emerging roles of transforming growth factor &amp;beta; signaling in wet age-related macular degeneration

Wang, Kai; Li, Haoran; Sun, Ruipu; Liu, Chaxian; Luo, Yunfei; Fu, Su; Ying, Ying

doi:10.1093/abbs/gmy145

Cited by 27 publications

(26 citation statements)

References 66 publications

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“…For example, our network analysis indicates that the top 10 miRNA are controlling genes associated with Interleukin and chemokine signaling, with both of these biological pathways involved in a plethora of retinal degenerative diseases ( Rutar et al, 2015 ; Wooff et al, 2019 ). Moreover, MAPK signaling and TGF-β have also been shown to play pivotal roles in the development of retinal degenerations ( Kyosseva, 2016 ; Wang et al, 2018 ), with both pathways showing a strong association with the targetome of the top 10 most highly expressed s-mEV-miRNAs. As the top 10 miRNAs in both dim-reared and photo-oxidative damage retinal s-mEV make up approximately 70% of the total s-mEV-MiRnome, it is not surprising that a reduction in s-mEV numbers during degeneration could lead to immune dysfunction due to inadequate gene regulation.…”

Section: Discussionmentioning

confidence: 99%

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

Wooff

Cioanca

Chu-Tan

et al. 2020

Front. Cell. Neurosci.

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Photoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases such as age-related macular degeneration (AMD). However, the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs, including exosomes, encapsulate and transfer microRNA (miRNA) to recipient cells and in this way can modulate the environment of recipient cells. Dysregulation of EVs however is correlated to a loss of cellular homeostasis and increased inflammation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina. Isolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion. Results demonstrated an inverse correlation between s-mEV concentration and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue, however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage. Taken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

Wooff

Cioanca

Chu-Tan

et al. 2020

Front. Cell. Neurosci.

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“…TGF-β is an important promoter of immune homeostasis and tolerance, which inhibits the expansion and function of many components of the immune response [86]. TGF-β superfamily members involves angiogenesis, inflammatory reactions, vascular fibrosis, immune responses and crosstalk with other signaling pathways in AMD pathogenesis [87]. TGF-β plays a vital role in the formation and development of CNV by Smad2/3-VEGF/TNF-α signaling pathway in wet AMD [88].…”

Section: Cytokinesmentioning

confidence: 99%

The Role of Inflammation in Age-Related Macular Degeneration

Tan¹,

Zou²,

Yoshida³

et al. 2020

Int. J. Biol. Sci.

146

103

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Age-related macular degeneration (AMD) is a blinding eye disease which incidence gradually increases with age. Inflammation participates in AMD pathogenesis, including choroidal neovascularization and geographic atrophy. It is also a kind of self-protective regulation from injury for the eyes. In this review, we described inflammation in AMD pathogenesis, summarized the roles played by inflammation-related cytokines, including pro-inflammatory and anti-inflammatory cytokines, as well as leukocytes (macrophages, dendritic cells, neutrophils, T lymphocytes and B lymphocytes) in the innate or adaptive immunity in AMD. Possible clinical applications such as potential diagnostic biomarkers and anti-inflammatory therapies were also discussed. This review overviews the inflammation as a target of novel effective therapies in treating AMD.

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“… 61 There are also reports of an emerging role of TGF-β in AMD and that TGF-β signaling pathways may be a target for treatment in, specifically, the neovascular form of advanced AMD. 62 Indeed, a TGF-β inhibitor has been shown to have a role in decreasing the development of choroidal neovascular (CNV) lesions in a rat model of CNV induction. 63 This family of proteins also has been found to be downregulated in the aqueous of patients with neovascular AMD.…”

Section: Discussionmentioning

confidence: 99%

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

Lynch

Wagner

Palestine

et al. 2020

Trans. Vis. Sci. Tech.

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Purpose To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3–48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03–49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-β family members. Conclusions We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational Relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

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Emerging roles of transforming growth factor β signaling in wet age-related macular degeneration

Cited by 27 publications

References 66 publications

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

The Role of Inflammation in Age-Related Macular Degeneration

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

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