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      Molecular Assessment of Epiretinal Membrane: Activated Microglia, Oxidative Stress and Inflammation

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          Abstract

          Fibrocellular membrane or epiretinal membrane (ERM) forms on the surface of the inner limiting membrane (ILM) in the inner retina and alters the structure and function of the retina. ERM formation is frequently observed in ocular inflammatory conditions, such as proliferative diabetic retinopathy (PDR) and retinal detachment (RD). Although peeling of the ERM is used as a surgical intervention, it can inadvertently distort the retina. Our goal is to design alternative strategies to tackle ERMs. As a first step, we sought to determine the composition of the ERMs by identifying the constituent cell-types and gene expression signature in patient samples. Using ultrastructural microscopy and immunofluorescence analyses, we found activated microglia, astrocytes, and Müller glia in the ERMs from PDR and RD patients. Moreover, oxidative stress and inflammation associated gene expression was significantly higher in the RD and PDR membranes as compared to the macular hole samples, which are not associated with inflammation. We specifically detected differential expression of hypoxia inducible factor 1-α ( HIF1-α), proinflammatory cytokines, and Notch, Wnt, and ERK signaling pathway-associated genes in the RD and PDR samples. Taken together, our results provide new information to potentially develop methods to tackle ERM formation.

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          Most cited references30

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          Retinal microglia: just bystander or target for therapy?

          Resident microglial cells can be regarded as the immunological watchdogs of the brain and the retina. They are active sensors of their neuronal microenvironment and rapidly respond to various insults with a morphological and functional transformation into reactive phagocytes. There is strong evidence from animal models and in situ analyses of human tissue that microglial reactivity is a common hallmark of various retinal degenerative and inflammatory diseases. These include rare hereditary retinopathies such as retinitis pigmentosa and X-linked juvenile retinoschisis but also comprise more common multifactorial retinal diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, and uveitis as well as neurological disorders with ocular manifestation. In this review, we describe how microglial function is kept in balance under normal conditions by cross-talk with other retinal cells and summarize how microglia respond to different forms of retinal injury. In addition, we present the concept that microglia play a key role in local regulation of complement in the retina and specify aspects of microglial aging relevant for chronic inflammatory processes in the retina. We conclude that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases of the retina.
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            Microglial activation in human diabetic retinopathy.

            To investigate microglial activation in human diabetic retinopathy. Paraffin sections from 21 eyes of 13 patients with diabetic background, preproliferative, or proliferative retinopathies and 10 normal eyes of 9 individuals were studied with immunolabeling of microglia with antibodies against HLA-DR antigen, CD45, or CD68. In the healthy human eyes, ramified microglial cells were scattered in the inner retinal layers. In eyes with diabetic retinopathy, the microglia were markedly increased in number and were hypertrophic at different stages of the disease. These cells clustered around the retinal vasculature, especially the dilated veins, microaneurysms, intraretinal hemorrhages, cotton-wool spots, optic nerve, and retinal and vitreal neovascularization. In some retinas with cystoid macular edema, microglia infiltrated the outer retina and subretinal space. Cells in the epiretinal membrane were also labeled with microglial markers. Microglia were activated at different stages of human diabetic retinopathy and optic neuropathy. Microglial perivasculitis was a prominent feature of the disease process. Activated microglia and microglial perivasculitis may play a role in vasculopathy and neuropathy in diabetic retinopathy.
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              Structural macromolecules and supramolecular organisation of the vitreous gel.

              The vitreous gel is a transparent extracellular matrix that fills the cavity behind the lens of the eye and is surrounded by and attached to the retina. This gel liquefies during ageing and in 25-30% of the oppulation the residual gel structure eventually collapses away from the posterior retina in a process called posterior retina in a process called posterior vitreous detachment. This process plays a pivotal role in a number of common blinding conditions including rhegmatogenous retinal detachment, proliferative diabetic retinopathy and macular hole formation. In order to understand the molecular events underlying vitreous liquefaction and posterior vitreous detachment and to develop new therapies it is important to understand the molecular basis of normal vitreous gel structure and how this is altered during ageing. It has previously been established that a dilute dispersion of thin (heterotypic) collagen fibrils is essential to the gel structure and that age-related vitreous liquefaction is intimately related to a process whereby these collagen fibrils aggregate. Collagen fibrils have a natural tendency to aggregate so a key question that has to be addressed is: what normally maintains the spacing of the collagen fibrils? In mammalian vitreous a network of hyaluronan normally fills the spaces between these collagen fibrils. This hyaluronan network can be removed without destroying the gel structure, so the hyaluronan is not essential for maintaining the spacing of the collagen fibrils although it probably does increase the mechanical resilience of the gel. The thin heterotypic collagen fibrils have a coating of non-covalently bound macromolecules which, along with the surface features of the collagen fibrils themselves, probably play a fundamental role in maintaining gel stability. They are likely to both maintain the short-range spacing of vitreous collagen fibrils and to link the fibrils together to form a contiguous network. A collagen fibril-associated macromolecule that may contribute to the maintenance of short-range spacing is opticin, a newly discovered extracellular matrix leucine-rich repeat protein. In addition, surface features of the collagen fibrils such as the chondroitin sulphate glycosaminoglycan chains of type IX collagen proteoglycan may also play an important role in maintaining fibril spacing. Furthering our knowledge of these and other components related to the surface of the heterotypic collagen fibrils will allow us to make important strides in understanding the macromolecular organisation of this unique and fascinating tissue. In addition, it will open up new therapeutic opportunities as it will allow the development of therapeutic reagents that can be used to modulate vitreous gel structure and thus treat a number of common, potentially blinding, ocular conditions.
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                23 July 2020
                August 2020
                : 9
                : 8
                : 654
                Affiliations
                [1 ]Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad 500034, India; svishwakarma17@ 123456gmail.com (S.V.); rkgupta@ 123456iimcb.gov.pl (R.K.G.)
                [2 ]Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
                [3 ]Ophthalmic Pathology Laboratory, L.V. Prasad Eye Institute, Hyderabad 500034, India; saumyajakati@ 123456lvpei.org
                [4 ]Smt. Kanuri Santhamma Retina Vitreous Centre, L.V. Prasad Eye Institute, Hyderabad 500034, India; drmudit@ 123456lvpei.org (M.T.); rajeev@ 123456lvpei.org (R.R.P.)
                [5 ]Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA; keith.reddig@ 123456umassmed.edu (K.R.); Gregory.Hendricks@ 123456umassmed.edu (G.H.)
                [6 ]Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; michael.volkert@ 123456umassmed.edu
                [7 ]Department of Ophthalmology & Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA; hemant.khanna@ 123456umassmed.edu
                Author notes
                [* ]Correspondence: jay.chhablani@ 123456gmail.com (J.C.); inderjeet@ 123456lvpei.org (I.K.); Tel.: +91-40-306-12607 or +91-40-306-12345 (J.C. & I.K.); Fax: +91-40-2354-8271 (J.C. & I.K.)
                [†]

                These authors contributed equally to this work.

                [‡]

                Present address: Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland.

                [§]

                Present address: Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

                Author information
                https://orcid.org/0000-0002-0209-3744
                https://orcid.org/0000-0002-3365-2588
                https://orcid.org/0000-0001-9211-917X
                https://orcid.org/0000-0002-0045-0912
                https://orcid.org/0000-0003-3660-5039
                Article
                antioxidants-09-00654
                10.3390/antiox9080654
                7465764
                32717933
                b51e2fcb-586e-4444-a01c-5d1ef3abcef6
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 June 2020
                : 21 July 2020
                Categories
                Article

                human retina,epiretinal membrane,internal limiting membrane,vitreoretinal surgery,macular hole,proliferative diabetic retinopathy

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