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Article ; Online: The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome.

Brandli, Alice / Vessey, Kirstan A / Fletcher, Erica L

2024 Volume 21, Issue 1, Page(s) 64

Abstract: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation ...

Abstract	Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation have been suggested to contribute to the pathogenesis of AMD, although the exact mechanism(s) and signalling pathways remain elusive. Pattern recognition receptors (PRRs) are essential activators of the innate immune system and drivers of para-inflammation. Of these PRRs, the two most prominent are (1) Toll-like receptors (TLR) and (2) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome have been found to modulate the progression of AMD. Mutations in TLR2 have been found to be associated with an increased risk of developing AMD. In animal models of AMD, inhibition of TLR and NLRP3 has been shown to reduce RPE cell death, inflammation and angiogenesis signalling, offering potential novel treatments for advanced AMD. Here, we examine the evidence for PRRs, TLRs2/3/4, and NLRP3-inflammasome pathways in macular degeneration pathogenesis.
MeSH term(s)	Animals ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Toll-Like Receptors ; Inflammation ; Macular Degeneration
Chemical Substances	Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Toll-Like Receptors
Language	English
Publishing date	2024-03-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-024-03055-1
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Article ; Online: Contribution of microglia and monocytes to the development and progression of age related macular degeneration.

Fletcher, Erica L

Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists)

2020 Volume 40, Issue 2, Page(s) 128–139

Abstract: Purpose: Age related macular degeneration (AMD) is the leading cause of irreversible vision loss in industrialised nations. Based on genetics, as well as proteome analysis of drusen, the role the innate immune system in the development and/or ... ...

Abstract	Purpose: Age related macular degeneration (AMD) is the leading cause of irreversible vision loss in industrialised nations. Based on genetics, as well as proteome analysis of drusen, the role the innate immune system in the development and/or progression of the disease is well established. Mononuclear phagocytes, such as microglia and monocytes, play critical roles in innate immunity. Here, the role of retinal microglia in mediating normal retinal function, and how these cells change with age is discussed, so as to understand their role in the development and progression of AMD. Recent findings: It is now known that microglia dynamically survey the neural environment, responding rapidly to even the most subtle neural injury. The dynamic and phagocytic roles of microglia can change with age contributing to alteration in the response of these cells to damage with age. Accumulation of innate immune cells in the subretinal space is a hallmark feature of the development of AMD, reflecting either an increase in migration of monocytes into the retina, or a failure of immune cell elimination from the retina. Furthermore, changes in phagocytic ability of immune cells could contribute to the accumulation of drusen deposits in the posterior eye. Summary: An overview of how retinal microglia maintain retinal homeostasis under normal conditions is provided, and then how they contribute to each stage of AMD. In addition, circulating monocytes are altered in those with AMD, contributing to the overall inflammatory state. Understanding the role of cells of the innate immune system in AMD may uncover novel therapeutic targets with which to reduce either the development or progression of disease.
MeSH term(s)	Disease Progression ; Humans ; Macular Degeneration/diagnosis ; Microglia/pathology ; Monocytes/pathology ; Retina/pathology
Language	English
Publishing date	2020-02-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	604564-9
ISSN	1475-1313 ; 0275-5408
ISSN (online)	1475-1313
ISSN	0275-5408
DOI	10.1111/opo.12671
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Article ; Online: Advances in understanding the mechanisms of retinal degenerations.

Fletcher, Erica L

Clinical & experimental optometry

2020

Abstract: Photoreceptor death is an important contributor to irreversible vision loss worldwide. In this review, I outline our work examining the role that purines, such as adenosine triphosphate (ATP), have in normal retinal function and in retinal disease. Our ... ...

Abstract	Photoreceptor death is an important contributor to irreversible vision loss worldwide. In this review, I outline our work examining the role that purines, such as adenosine triphosphate (ATP), have in normal retinal function and in retinal disease. Our work shows that the actions of ATP, mediated by P2X receptors, are expressed in various retinal layers including photoreceptor terminals, and when stimulated by excessive levels of ATP is associated with rapid death of neurons. Treatment with a compound that blocks the action of P2X and some P2Y receptors reduces photoreceptor death in a mouse model of retinal degeneration. Our observations not only provide a means for developing a potential treatment for reducing photoreceptor death, but also provides a novel way of studying the neural plasticity effects that develop in the inner retina following photoreceptor death. There are a range of inner retinal changes that could influence the effectiveness of retinal prostheses. Indeed, using an ATP-induced degeneration model, we established that the amount of electrical stimulation required to elicit a response in the visual cortex was affected by the level of glial scarring. However, changes in P2X7 receptor expression by OFF ganglion cells during retinal degeneration can also be exploited by photoswitches to restore light sensitivity to degenerated retinae. Finally, our work has also considered how P2X7 expression by innate immune cells, and its role as a scavenger receptor, contributes to age-related macular degeneration (AMD). Our results show that loss of P2X7 function is associated with thickening of Bruch's membrane as well as increased risk of advanced disease in people with AMD. Overall, our work over the last 20 years highlights the importance of purinergic signalling in normal retinal function and retinal disease and suggest that developing therapies that target P2X7 function could be of benefit for these diseases.
Language	English
Publishing date	2020-10-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	639275-1
ISSN	1444-0938 ; 0816-4622
ISSN (online)	1444-0938
ISSN	0816-4622
DOI	10.1111/cxo.13146
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Article: Loss of Müller cell glutamine synthetase immunoreactivity is associated with neuronal changes in late-stage retinal degeneration.

Reynisson, Hallur / Kalloniatis, Michael / Fletcher, Erica L / Shivdasani, Mohit N / Nivison-Smith, Lisa

Frontiers in neuroanatomy

2023 Volume 17, Page(s) 997722

Abstract: Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal ... ...

Abstract	Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers. Methods: Aged Rd1 mice retinae (P150 - P536, Results: Glutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 - P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity. Conclusion: These findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development.
Language	English
Publishing date	2023-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452969-2
ISSN	1662-5129
ISSN	1662-5129
DOI	10.3389/fnana.2023.997722
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Article ; Online: Anomalies in neurovascular coupling during early diabetes: A review.

Fletcher, Erica L / Dixon, Michael A / Mills, Samuel A / Jobling, Andrew I

Clinical & experimental ophthalmology

2022 Volume 51, Issue 1, Page(s) 81–91

Abstract: Diabetic retinopathy is the most feared complication for those with diabetes. Although visible vascular pathology traditionally defines the management of this condition, it is now recognised that a range of cellular changes occur in the retina from an ... ...

Abstract	Diabetic retinopathy is the most feared complication for those with diabetes. Although visible vascular pathology traditionally defines the management of this condition, it is now recognised that a range of cellular changes occur in the retina from an early stage of diabetes. One of the most significant functional changes that occurs in those with diabetes is a loss of vasoregulation in response to changes in neural activity. There are several retinal cell types that are critical for mediating so-called neurovascular coupling, including Müller cells, microglia and pericytes. Although there is a great deal of evidence that suggests that Müller cells are integral to regulating the vasculature, they only modulate part of the vascular tree, highlighting the complexity of vasoregulation within the retina. Recent studies suggest that retinal immune cells, microglia, play an important role in mediating vasoconstriction. Importantly, retinal microglia contact both the vasculature and neural synapses and induce vasoconstriction in response to neurally expressed chemokines such as fractalkine. This microglial-dependent regulation occurs via the vasomediator angiotensinogen. Diabetes alters the way microglia regulate the retinal vasculature, by increasing angiotensinogen expression, causing capillary vasoconstriction and contributing to a loss of vascular reactivity to physiological signals. This article summarises recent studies showing changes in vascular regulation during diabetes, the potential mechanisms by which this occurs and the significance of these early changes to the progression of diabetic retinopathy.
MeSH term(s)	Humans ; Diabetic Retinopathy ; Angiotensinogen/metabolism ; Neurovascular Coupling ; Retina/pathology ; Retinal Vessels/pathology ; Microglia/metabolism ; Microglia/pathology ; Diabetes Mellitus
Chemical Substances	Angiotensinogen (11002-13-4)
Language	English
Publishing date	2022-11-18
Publishing country	Australia
Document type	Journal Article ; Review
ZDB-ID	2014008-3
ISSN	1442-9071 ; 1442-6404
ISSN (online)	1442-9071
ISSN	1442-6404
DOI	10.1111/ceo.14190
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Article ; Online: What neurochemistry tells us about the retina.

Fletcher, Erica L

Clinical & experimental optometry

2013 Volume 96, Issue 3, Page(s) 257–258

MeSH term(s)	Amino Acids/analysis ; Humans ; Retina/chemistry ; Retinal Diseases/metabolism
Chemical Substances	Amino Acids
Language	English
Publishing date	2013-05
Publishing country	Australia
Document type	Comment ; Editorial
ZDB-ID	639275-1
ISSN	1444-0938 ; 0816-4622
ISSN (online)	1444-0938
ISSN	0816-4622
DOI	10.1111/cxo.12070
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Article: The Contribution of Microglia to the Development and Maturation of the Visual System.

Dixon, Michael A / Greferath, Ursula / Fletcher, Erica L / Jobling, Andrew I

Frontiers in cellular neuroscience

2021 Volume 15, Page(s) 659843

Abstract: Microglia, the resident immune cells of the central nervous system (CNS), were once considered quiescent cells that sat in readiness for reacting to disease and injury. Over the last decade, however, it has become clear that microglia play essential ... ...

Abstract	Microglia, the resident immune cells of the central nervous system (CNS), were once considered quiescent cells that sat in readiness for reacting to disease and injury. Over the last decade, however, it has become clear that microglia play essential roles in maintaining the normal nervous system. The retina is an easily accessible part of the central nervous system and therefore much has been learned about the function of microglia from studies in the retina and visual system. Anatomically, microglia have processes that contact all synapses within the retina, as well as blood vessels in the major vascular plexuses. Microglia contribute to development of the visual system by contributing to neurogenesis, maturation of cone photoreceptors, as well as refining synaptic contacts. They can respond to neural signals and in turn release a range of cytokines and neurotrophic factors that have downstream consequences on neural function. Moreover, in light of their extensive contact with blood vessels, they are also essential for regulation of vascular development and integrity. This review article summarizes what we have learned about the role of microglia in maintaining the normal visual system and how this has helped in understanding their role in the central nervous system more broadly.
Language	English
Publishing date	2021-04-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2021.659843
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Article ; Online: Transcriptomic analysis of choroidal neovascularization reveals dysregulation of immune and fibrosis pathways that are attenuated by a novel anti-fibrotic treatment.

Brandli, Alice / Khong, Fay L / Kong, Roy C K / Kelly, Darren J / Fletcher, Erica L

Scientific reports

2022 Volume 12, Issue 1, Page(s) 859

Abstract: Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Current treatments that target blood vessel growth have not been able to treat subretinal fibrosis and nAMD patients continue to lose ... ...

Abstract	Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Current treatments that target blood vessel growth have not been able to treat subretinal fibrosis and nAMD patients continue to lose vision. The molecular mechanisms involved in the development of fibrotic lesions in nAMD are not well understood. The aim of this study was to further understand subretinal fibrosis in the laser photocoagulation model of choroidal neovascularization (CNV) by studying the whole transcriptome of the RPE/choroid following CNV and the application of an anti-fibrotic following CNV. Seven days after laser induced CNV, RPE and choroid tissue was separated and underwent RNAseq. Differential expression analysis and pathway analysis revealed an over representation of immune signalling and fibrotic associated pathways in CNV compared to control RPE/choroid tissue. Comparisons between the mouse CNV model to human CNV revealed an overlap in upregulated expression for immune genes (Ccl2, Ccl8 and Cxcl9) and extracellular matrix remodeling genes (Comp, Lrcc15, Fndc1 and Thbs2). Comparisons between the CNV model and other fibrosis models showed an overlap of over 60% of genes upregulated in either lung or kidney mouse models of fibrosis. Treatment of CNV using a novel cinnamoyl anthranilate anti-fibrotic (OCX063) in the laser induced CNV model was selected as this class of drugs have previously been shown to target fibrosis. CNV lesion leakage and fibrosis was found to be reduced using OCX063 and gene expression of genes within the TGF-beta signalling pathway. Our findings show the presence of fibrosis gene expression pathways present in the laser induced CNV mouse model and that anti-fibrotic treatments offer the potential to reduce subretinal fibrosis in AMD.
MeSH term(s)	Animals ; Antifibrotic Agents/pharmacology ; Antifibrotic Agents/therapeutic use ; Cartilage Oligomeric Matrix Protein ; Chemokine CCL2 ; Chemokine CCL8 ; Choroidal Neovascularization/drug therapy ; Choroidal Neovascularization/genetics ; Choroidal Neovascularization/immunology ; Choroidal Neovascularization/pathology ; Disease Models, Animal ; Fibrosis/genetics ; Gene Expression ; Gene Expression Profiling ; Immunity/genetics ; Mice, Inbred C57BL ; Retina/pathology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Transcriptome/genetics ; Mice
Chemical Substances	Antifibrotic Agents ; Cartilage Oligomeric Matrix Protein ; Ccl2 protein, mouse ; Ccl8 protein, mouse ; Chemokine CCL2 ; Chemokine CCL8 ; Comp protein, mouse
Language	English
Publishing date	2022-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-04845-4
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Article ; Online: Aging induces cell loss and a decline in phagosome processing in the mouse retinal pigment epithelium.

Ma, Jessica Y W / Greferath, Ursula / Wong, Josephine H C / Fothergill, Linda J / Jobling, Andrew I / Vessey, Kirstan A / Fletcher, Erica L

Neurobiology of aging

2023 Volume 128, Page(s) 1–16

Abstract: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and dysfunction in the retinal pigment epithelium (RPE) with age is known to contribute to disease development. The aim of this study was to investigate how the C57BL/ ... ...

Abstract	Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and dysfunction in the retinal pigment epithelium (RPE) with age is known to contribute to disease development. The aim of this study was to investigate how the C57BL/6J mouse RPE changes with age. RPE structure was found to change with age and eccentricity, with cell size increasing, nuclei lost, and tight junctions altered in the peripheral retina. Phagocytosis of photoreceptor outer segments (POS) by the RPE was investigated using gene expression analysis and histology. RNA-Seq transcriptomic gene profiling of the RPE showed a downregulation of genes involved in phagosome processing and histological analysis showed a decline in phagosome-lysosome association in the aged tissue. In addition, failures in the autophagy pathway that modulates intracellular waste degradation were observed in the aged RPE tissue. These findings highlight that RPE cell loss and slowing of POS processing contribute to RPE dysfunction with age and may predispose the aging eye to AMD development.
MeSH term(s)	Mice ; Animals ; Retinal Pigment Epithelium ; Mice, Inbred C57BL ; Phagocytosis/genetics ; Phagosomes/metabolism ; Aging/genetics
Language	English
Publishing date	2023-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2023.03.003
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Zs.A 1685: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Genetics of reticular pseudodrusen in age-related macular degeneration.

Farashi, Samaneh / Ansell, Brendan R E / Wu, Zhichao / Abbott, Carla J / Pébay, Alice / Fletcher, Erica L / Guymer, Robyn H / Bahlo, Melanie

Trends in genetics : TIG

2022 Volume 38, Issue 4, Page(s) 312–316

Abstract: Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established ...

Abstract	Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.
MeSH term(s)	Humans ; Macular Degeneration/complications ; Macular Degeneration/genetics ; Retinal Drusen/complications ; Retinal Drusen/genetics ; Risk Factors
Language	English
Publishing date	2022-01-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2022.01.003
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