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Li C, Wang B. Role of P2X7R in Retinal Diseases: A Review. Immun Inflamm Dis 2025; 13:e70203. [PMID: 40396593 DOI: 10.1002/iid3.70203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/16/2025] [Accepted: 04/25/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND P2X purinoceptor 7 receptor (P2X7R) is an ATP-gated ion channel that, upon activation by ATP, triggers the release of inflammatory mediators and induces apoptosis in cells. This channel plays a crucial role in the onset and progression of various diseases. Recently, there has been a growing body of research focused on the function of P2X7R receptors in ophthalmic conditions, particularly concerning retinal diseases such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. OBJECTIVE This article is to provide a comprehensive review of the advancements in the study of P2X7R and its association with retinal diseases, elucidating its role in these conditions and identifying potential avenues for future research. METHODS Electronic databases, including PubMed, Web of Science, and Wan fang Data were searched for relevant literature. The following keywords were used: "P2X7R", Age-related macular degeneration", "Diabetic retinopathy", "Retinitis pigmentosa". Both preclinical and clinical studies were included to provide a holistic understanding of P2X7R's role in retinal pathology. RESULTS P2X7R activation exacerbates retinal diseases by promoting inflammation and apoptosis. However, its role in disease progression and homeostasis complicates therapeutic targeting, highlighting the need for selective inhibitors and further research into its context-dependent functions. CONCLUSION P2X7R plays a critical role in the pathogenesis of retinal diseases. At the same time, preclinical studies suggest that P2X7R inhibition holds promise as a therapeutic strategy. Future research should focus on developing selective P2X7R inhibitors, elucidating the receptor's role in different disease stages, and identifying biomarkers to guide personalized treatment. Addressing these challenges will be essential for translating P2X7R-targeted therapies into clinical practice and improving outcomes for patients with retinal diseases.
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Affiliation(s)
- Chunli Li
- Department of Ophthalmology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Binsheng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Garton T, Smith MD, Kesharwani A, Gharagozloo M, Oh S, Na CH, Absinta M, Reich DS, Zack DJ, Calabresi PA. Myeloid lineage C3 induces reactive gliosis and neuronal stress during CNS inflammation. Nat Commun 2025; 16:3481. [PMID: 40216817 PMCID: PMC11992029 DOI: 10.1038/s41467-025-58708-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Complement component C3 mediates pathology in CNS neurodegenerative diseases. Here we use scRNAseq of sorted C3-reporter positive cells from mouse brain and optic nerve to characterize C3 producing glia in experimental autoimmune encephalomyelitis (EAE), a model in which peripheral immune cells infiltrate the CNS, causing reactive gliosis and neuro-axonal pathology. We find that C3 expression in the early inflammatory stage of EAE defines disease-associated glial subtypes characterized by increased expression of genes associated with mTOR activation and cell metabolism. This pro-inflammatory subtype is abrogated with genetic C3 depletion, a finding confirmed with proteomic analyses. In addition, early optic nerve axonal injury and retinal ganglion cell oxidative stress, but not loss of post-synaptic density protein 95, are ameliorated by selective deletion of C3 in myeloid cells. These data suggest that in addition to C3b opsonization of post synaptic proteins leading to neuronal demise, C3 activation is a contributor to reactive glia in the optic nerve.
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Affiliation(s)
- Thomas Garton
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Matthew D Smith
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ajay Kesharwani
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Marjan Gharagozloo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Sungtaek Oh
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Chan-Hyun Na
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Martina Absinta
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Reserach Hospital, Milan, Italy
| | - Daniel S Reich
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Donald J Zack
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Peter A Calabresi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, 21205, USA.
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Hector M, Behnke V, Dabrowska-Schlepp P, Busch A, Schaaf A, Langmann T, Wolf A. Moss-derived human complement factor H modulates retinal immune response and attenuates retinal degeneration. J Neuroinflammation 2025; 22:104. [PMID: 40217267 PMCID: PMC11992837 DOI: 10.1186/s12974-025-03418-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 03/12/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND AMD is a multifactorial progressive disease of the central retina that leads to severe vision loss among the elderly. Genome-wide association studies in AMD patients and preclinical data have identified a dysregulated complement system and aberrant microglia responses in the pathogenesis of AMD. Specifically, a genetic variant in the complement factor H (CFH) gene, an important inhibitor of the alternative complement pathway, confers the strongest risk for AMD. Here, we investigated whether moss-derived recombinant human CFH proteins, termed CPV-101 and CPV-104, can modulate microglia reactivity and limit retinal degeneration in a murine light damage paradigm mimicking important features of AMD. METHODS Two glycosylated human recombinant CFH proteins CPV101, and CPV-104 were produced in moss suspension cultures. In addition, glycans of the CPV-104 variant are sialylated, an optimization that makes CPV-104 an analog of human CFH. BALB/cJ mice received intravitreal injections of 5 µg CPV-101 and CPV-104 or vehicle, starting 1 day prior to exposure to 10,000 lx white light for 30 min. The effects of CPV-101 and CPV-104 treatment on mononuclear phagocyte and Müller cell reactivity were analyzed by immunostainings of retinal sections and flat mounts. Gene expression of microglia markers was analyzed using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT); Blue Peak Autofluorescence (BAF); terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis. RESULTS Light-exposed mice treated with moss-derived recombinant human full-length CFH showed reduced complement activation and MAC deposition in the retina. Concomitantly, mononuclear phagocyte and Müller cell reactivity in light-exposed retinas were also ameliorated upon CFH substitution. Moreover, attenuated light-induced retinal degeneration was detected in mice that received moss-derived CFH. CONCLUSION Modulating the alternative complement pathway using moss-derived recombinant human full-length CFH variant CPV-101 and CPV-104 counter-regulate gliosis and attenuates light-induced retinal degeneration, highlighting a promising concept for the treatment of AMD patients.
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Affiliation(s)
- Mandy Hector
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany
| | - Verena Behnke
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany
| | | | - Andreas Busch
- Eleva GmbH, Hans-Bunte-Straße 19, 79108, Freiburg, Germany
| | - Andreas Schaaf
- Eleva GmbH, Hans-Bunte-Straße 19, 79108, Freiburg, Germany
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Anne Wolf
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
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van Koeverden AK, Afiat BC, Nguyen CT, Bui BV, Lee PY. Understanding how ageing impacts ganglion cell susceptibility to injury in glaucoma. Clin Exp Optom 2024; 107:147-155. [PMID: 37980904 DOI: 10.1080/08164622.2023.2279734] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 10/31/2023] [Indexed: 11/21/2023] Open
Abstract
Glaucoma is a leading cause of blindness worldwide, with a marked increase in prevalence with advancing age. Due to the multifactorial nature of glaucoma pathogenesis, dissecting how ageing impacts upon glaucoma risk requires analysis and synthesis of evidence from a vast literature. While there is a wealth of human clinical studies examining glaucoma pathogenesis and why older patients have increased risk, many aspects of the disease such as adaptations of retinal ganglion cells to stress, autophagy and the role of glial cells in glaucoma, require the use of animal models to study the complex cellular processes and interactions. Additionally, the accelerated nature of ageing in rodents facilitates the longitudinal study of changes that would not be feasible in human clinical studies. This review article examines evidence derived predominantly from rodent models on how the ageing process impacts upon various aspects of glaucoma pathology from the retinal ganglion cells themselves, to supporting cells and tissues such as glial cells, connective tissue and vasculature, in addition to oxidative stress and autophagy. An improved understanding of how ageing modifies these factors may lead to the development of different therapeutic strategies that target specific risk factors or processes involved in glaucoma.
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Affiliation(s)
- Anna K van Koeverden
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Brianna C Afiat
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Christine To Nguyen
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Bang V Bui
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Pei Ying Lee
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia
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Patel SB, Heier JS, Chaudhary V, Wykoff CC. Treatment of geographic atrophy: an update on data related to pegcetacoplan. Curr Opin Ophthalmol 2024; 35:64-72. [PMID: 37815317 DOI: 10.1097/icu.0000000000000845] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
PURPOSE OF REVIEW Geographic atrophy is an advanced and currently untreatable form of age-related macular degeneration (AMD), which leads to significant compromise of visual function and quality of life. Dysregulation of the complement cascade has been directly implicated in AMD pathogenesis. Pegcetacoplan is a pegylated highly selective bicyclic peptide that inhibits the cleavage of complement component 3 (C3), which represents a key step in propagation of the complement cascade. The phase 2 FILLY trial as well as the phase 3 OAKS and DERBY trials have evaluated the safety and efficacy of pegcetacoplan for the treatment of GA. RECENT FINDINGS The FILLY, OAKS and DERBY trials have demonstrated that local inhibition of C3 cleavage with pegcetacoplan can reduce geographic atrophy lesion growth compared with sham with an effect size of approximately 11-35% depending on the specific trial and specific geographic atrophy phenotype considered. Overall pegcetacoplan has appeared to be well tolerated with the notable side effect of a dose-dependent increase in the rate of exudative AMD development in treated eyes. SUMMARY The FILLY, OAKS and DERBY trials have demonstrated that pegcetacoplan is a potentially viable treatment for geographic atrophy. Additional data from the 2-year outcomes of DERBY and OAKS as well as data from the ongoing 3-year GALE extension study will provide additional insights into the potential therapeutic benefit of pegcetacoplan. Future studies assessing complement inhibition at earlier stages of AMD, with the goal of preventing geographic atrophy formation, are warranted.
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Affiliation(s)
- Sagar B Patel
- Retina Consultants of Texas, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
| | - Jeffrey S Heier
- Ophthalmic Consultants of Boston, Boston, Massachusetts, USA
| | - Varun Chaudhary
- Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Charles C Wykoff
- Retina Consultants of Texas, Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas
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Fanelli G, Romano M, Lombardi G, Sacks SH. Soluble Collectin 11 (CL-11) Acts as an Immunosuppressive Molecule Potentially Used by Stem Cell-Derived Retinal Epithelial Cells to Modulate T Cell Response. Cells 2023; 12:1805. [PMID: 37443840 PMCID: PMC10341155 DOI: 10.3390/cells12131805] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/30/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Retinal pigment epithelium (RPE) cell allotransplantation is seen as a possible solution to retinal diseases. However, the RPE-complement system triggered by the binding of collectin-11 (CL-11) is a potential barrier for RPE transplantation as the complement-mediated inflammatory response may promote T cell recognition. To address this, we investigated the role of CL-11 on T cell immuno-response. We confirmed that RPE cells up-regulated MHC class I and expressed MHC class II molecules in an inflammatory setting. Co-cultures of RPE cells with T cells led to the inhibition of T cell proliferation. We found that CL-11 was partially responsible for this effect as T cell binding of CL-11 inhibited T cell proliferation in association with the downregulation of CD28. We also found that the suppressive action of CL-11 was abrogated in the presence of the RGD peptide given to block the T cell binding of CL-11 by its collagen-like domain. Because RPE cells can bind and secrete CL-11 under stress conditions, we postulate that soluble CL-11 contributes to the immunosuppressive properties of RPE cells. The investigation of this dual biological activity of CL-11, namely as a trigger of the complement cascade and a modulator of T cell responses, may provide additional clues about the mechanisms that orchestrate the immunogenic properties of RPE cells.
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Affiliation(s)
- Giorgia Fanelli
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College, London SE1 9RT, UK; (M.R.); (G.L.); (S.H.S.)
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Dos Santos FM, Ciordia S, Mesquita J, de Sousa JPC, Paradela A, Tomaz CT, Passarinha LAP. Vitreous humor proteome: unraveling the molecular mechanisms underlying proliferative and neovascular vitreoretinal diseases. Cell Mol Life Sci 2022; 80:22. [PMID: 36585968 PMCID: PMC11072707 DOI: 10.1007/s00018-022-04670-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 11/09/2022] [Accepted: 12/12/2022] [Indexed: 01/01/2023]
Abstract
Proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and neovascular age-related macular degeneration (nAMD) are among the leading causes of blindness. Due to the multifactorial nature of these vitreoretinal diseases, omics approaches are essential for a deeper understanding of the pathophysiologic processes underlying the evolution to a proliferative or neovascular etiology, in which patients suffer from an abrupt loss of vision. For many years, it was thought that the function of the vitreous was merely structural, supporting and protecting the surrounding ocular tissues. Proteomics studies proved that vitreous is more complex and biologically active than initially thought, and its changes reflect the physiological and pathological state of the eye. The vitreous is the scenario of a complex interplay between inflammation, fibrosis, oxidative stress, neurodegeneration, and extracellular matrix remodeling. Vitreous proteome not only reflects the pathological events that occur in the retina, but the changes in the vitreous itself play a central role in the onset and progression of vitreoretinal diseases. Therefore, this review offers an overview of the studies on the vitreous proteome that could help to elucidate some of the pathological mechanisms underlying proliferative and/or neovascular vitreoretinal diseases and to find new potential pharmaceutical targets.
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Affiliation(s)
- Fátima Milhano Dos Santos
- Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal.
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CNB-CSIC), Unidad de Proteomica, Calle Darwin 3, Campus de Cantoblanco, 28049, Madrid, Spain.
| | - Sergio Ciordia
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CNB-CSIC), Unidad de Proteomica, Calle Darwin 3, Campus de Cantoblanco, 28049, Madrid, Spain
| | - Joana Mesquita
- Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal
| | - João Paulo Castro de Sousa
- Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal
- Department of Ophthalmology, Centro Hospitalar de Leiria, 2410-197, Leiria, Portugal
| | - Alberto Paradela
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CNB-CSIC), Unidad de Proteomica, Calle Darwin 3, Campus de Cantoblanco, 28049, Madrid, Spain
| | - Cândida Teixeira Tomaz
- Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal
- C4-UBI, Cloud Computing Competence Centre, University of Beira Interior, 6200-501, Covilhã, Portugal
- Chemistry Department, Faculty of Sciences, Universidade da Beira Interior, 6201-001, Covilhã, Portugal
| | - Luís António Paulino Passarinha
- Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal.
- Associate Laboratory i4HB, Faculdade de Ciências e Tecnologia, Institute for Health and Bioeconomy, Universidade NOVA, 2819-516, Caparica, Portugal.
- UCIBIO-Applied Molecular Biosciences Unit, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal.
- Pharmaco-Toxicology Laboratory, UBIMedical, Universidade da Beira Interior, 6200-000, Covilhã, Portugal.
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Wendimu MY, Hooks SB. Microglia Phenotypes in Aging and Neurodegenerative Diseases. Cells 2022; 11:2091. [PMID: 35805174 PMCID: PMC9266143 DOI: 10.3390/cells11132091] [Citation(s) in RCA: 159] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 06/24/2022] [Accepted: 06/29/2022] [Indexed: 02/08/2023] Open
Abstract
Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.
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Affiliation(s)
| | - Shelley B. Hooks
- Hooks Lab, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA;
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Parker A, Romano S, Ansorge R, Aboelnour A, Le Gall G, Savva GM, Pontifex MG, Telatin A, Baker D, Jones E, Vauzour D, Rudder S, Blackshaw LA, Jeffery G, Carding SR. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. MICROBIOME 2022; 10:68. [PMID: 35501923 PMCID: PMC9063061 DOI: 10.1186/s40168-022-01243-w] [Citation(s) in RCA: 179] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/04/2022] [Indexed: 05/11/2023]
Abstract
BACKGROUND Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. METHODS Using fecal microbiota transplantation, we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing. RESULTS We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota. CONCLUSIONS These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut-brain and gut-retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life. Video abstract.
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Affiliation(s)
- Aimée Parker
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK.
| | - Stefano Romano
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Rebecca Ansorge
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Asmaa Aboelnour
- Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
| | - Gwenaelle Le Gall
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
| | - George M Savva
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | | | - Andrea Telatin
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - David Baker
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Emily Jones
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - David Vauzour
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK
| | - Steven Rudder
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - L Ashley Blackshaw
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK
| | - Glen Jeffery
- Institute of Ophthalmology, University College London, London, EC1V 9EL, UK
| | - Simon R Carding
- Gut Microbes and Health Research Programme, Quadram Institute, Norwich, NR4 7UQ, UK.
- Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ, UK.
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Abstract
The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3's functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3's relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.
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Affiliation(s)
- Benjamin J Kim
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Tianyu Liu
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - John D Lambris
- Department of Laboratory Medicine and Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Reinehr S, Doerner JD, Mueller-Buehl AM, Koch D, Fuchshofer R, Dick HB, Joachim SC. Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model. Front Cell Neurosci 2021; 15:718087. [PMID: 34867198 PMCID: PMC8637215 DOI: 10.3389/fncel.2021.718087] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Glaucoma is a complex neurodegenerative disease leading to a loss of retinal ganglion cells (RGCs) and optic nerve axons. An activation of the complement system seems to contribute to cell loss in this disease. Hence, we investigated a possible initiation of the complement system and the cytokine response in the βB1-CTGF glaucoma model. In these mice, intraocular pressure is elevated, which is the main glaucoma risk factor in patients, and RGC loss occurs at 15 weeks of age. Therefore, quantitative real-time PCR and immunohistological experiments were performed in 5-, 10-, and 15-week-old βB1-CTGF animals and their corresponding wildtypes (WT) to analyze the expression of several complement system factors. We could show that mRNA levels of the terminal complement pathway components C3 and C5 (Hc) were upregulated at 10 weeks. In accordance, more C3+ and membrane attack complex+ cells were observed in transgenic retinae. Further, the C5a receptor anaphylatoxin receptor (C5ar) and the complement component C5a receptor 1 (C5ar1; CD88) mRNA levels were upregulated in 10- and 15-week-old βB1-CTGF mice. Interestingly, all three activation routes of the complement system were elevated in βB1-CTGF mice at some age. Especially C1q, as a marker of the classical pathway, was significantly increased at all investigated ages. Furthermore, mRNA expression levels of interferon-γ (Infg) were upregulated at 5 weeks, while Cxcl1 and Cxcl2 mRNA levels were upregulated at 10 and 15 weeks. The mRNA levels of the chemokines Cxcl10 were increased at all ages in βB1-CTGF mice. These results lead to the assumption that in these transgenic mice, a complement activation mainly through the classical pathway as well as a cytokine response plays a major role in cell death.
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Affiliation(s)
- Sabrina Reinehr
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Johanna D. Doerner
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Ana M. Mueller-Buehl
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Dennis Koch
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Rudolf Fuchshofer
- Institute of Human Anatomy and Embryology, University Regensburg, Regensburg, Germany
| | - H. Burkhard Dick
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Stephanie C. Joachim
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
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12
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Feng L, Nie K, Huang Q, Fan W. Complement factor H deficiency combined with smoking promotes retinal degeneration in a novel mouse model. Exp Biol Med (Maywood) 2021; 247:77-86. [PMID: 34775843 DOI: 10.1177/15353702211052245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Age-related macular degeneration is the leading cause of blindness in the elderly. The Y402H polymorphism in complement factor H promotes disease-like pathogenesis, and a Cfh+/- murine model can replicate this phenotype, but only after two years. We reasoned that by combining CFH deficiency with cigarette smoke exposure, we might be able to accelerate disease progression to facilitate preclinical research in this disease. Wild-type and Cfh+/- mice were exposed to nose-only cigarette smoke for three months. Retinal tissue morphology and visual function were evaluated by optical coherence tomography, fundus photography and autofluorescence, and electroretinogram. Retinal pigment epithelial cell phenotype and ultrastructure were evaluated by immunofluorescence staining and transmission electron microscopy. Cfh+/- smoking mice showed a dome-like protruding lesion at the ellipsoid zone (drusen-like deposition), many retinal hyper-autofluorescence spots, and a marked decrease in A- and B-wave amplitudes. Compared with non-smoking mice, wild-type and Cfh+/- smoking mice showed sub-retinal pigment epithelium complement protein 3 deposition, activation of microglia, metabolic waste accumulation, and impairment of tight junctions. Microglia cells migrated into the photoreceptor outer segment layer in Cfh+/- smoking mice showed increased activation. Our results suggest that exposing Cfh+/- mice to smoking leads to earlier onset of age-related macular degeneration than in other animal models, which may facilitate preclinical research into the pathophysiology and treatment of this disease.
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Affiliation(s)
- Liwen Feng
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China.,Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kailai Nie
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China.,Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qing Huang
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Wei Fan
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China
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13
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Gallenga CE, Lonardi M, Pacetti S, Violanti SS, Tassinari P, Di Virgilio F, Tognon M, Perri P. Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa. Antioxidants (Basel) 2021; 10:antiox10060848. [PMID: 34073310 PMCID: PMC8229325 DOI: 10.3390/antiox10060848] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/13/2021] [Accepted: 05/20/2021] [Indexed: 12/17/2022] Open
Abstract
Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor’s daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.
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Affiliation(s)
- Carla Enrica Gallenga
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.E.G.); (F.D.V.); (M.T.)
| | - Maria Lonardi
- Department of Specialized Surgery, Section of Ophthalmology, Sant’Anna University Hospital, 44121 Ferrara, Italy; (M.L.); (S.P.); (P.T.)
| | - Sofia Pacetti
- Department of Specialized Surgery, Section of Ophthalmology, Sant’Anna University Hospital, 44121 Ferrara, Italy; (M.L.); (S.P.); (P.T.)
| | - Sara Silvia Violanti
- Department of Head and Neck, Section of Ophthalmology, San Paolo Hospital, 17100 Savona, Italy;
| | - Paolo Tassinari
- Department of Specialized Surgery, Section of Ophthalmology, Sant’Anna University Hospital, 44121 Ferrara, Italy; (M.L.); (S.P.); (P.T.)
| | - Francesco Di Virgilio
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.E.G.); (F.D.V.); (M.T.)
| | - Mauro Tognon
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy; (C.E.G.); (F.D.V.); (M.T.)
| | - Paolo Perri
- Department of Neuroscience and Rehabilitation, Section of Ophthalmology, University of Ferrara, 44121 Ferrara, Italy
- Correspondence:
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14
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Aggio-Bruce R, Chu-Tan JA, Wooff Y, Cioanca AV, Schumann U, Natoli R. Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration. Mol Neurobiol 2021; 58:835-854. [PMID: 33037565 PMCID: PMC7843561 DOI: 10.1007/s12035-020-02158-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/01/2020] [Indexed: 01/14/2023]
Abstract
Although extensively investigated in inflammatory conditions, the role of pro-inflammatory microRNAs (miRNAs), miR-155 and miR-146a, has not been well-studied in retinal degenerative diseases. We therefore aimed to explore the role and regulation of these miRNA in the degenerating retina, with a focus on miR-155. C57BL/6J mice were subjected to photo-oxidative damage for up to 5 days to induce focal retinal degeneration. MiR-155 expression was quantified by qRT-PCR in whole retina, serum, and small-medium extracellular vesicles (s-mEVs), and a PrimeFlow™ assay was used to identify localisation of miR-155 in retinal cells. Constitutive miR-155 knockout (KO) mice and miR-155 and miR-146a inhibitors were utilised to determine the role of these miRNA in the degenerating retina. Electroretinography was employed as a measure of retinal function, while histological quantification of TUNEL+ and IBA1+ positive cells was used to quantify photoreceptor cell death and infiltrating immune cells, respectively. Upregulation of miR-155 was detected in retinal tissue, serum and s-mEVs in response to photo-oxidative damage, localising to the nucleus of a subset of retinal ganglion cells and glial cells and in the cytoplasm of photoreceptors. Inhibition of miR-155 showed increased function from negative controls and a less pathological pattern of IBA1+ cell localisation and morphology at 5 days photo-oxidative damage. While neither dim-reared nor damaged miR-155 KO animals showed retinal histological difference from controls, following photo-oxidative damage, miR-155 KO mice showed increased a-wave relative to controls. We therefore consider miR-155 to be associated with the inflammatory response of the retina in response to photoreceptor-specific degeneration.
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Affiliation(s)
- Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia
- The Australian National University Medical School, Mills Road, Australian Capital Territory, Acton, 2601, Australia
| | - Joshua A Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia
- The Australian National University Medical School, Mills Road, Australian Capital Territory, Acton, 2601, Australia
| | - Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia
- The Australian National University Medical School, Mills Road, Australian Capital Territory, Acton, 2601, Australia
| | - Adrian V Cioanca
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia
| | - Ulrike Schumann
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, Australian Capital Territory, 2601, Australia.
- The Australian National University Medical School, Mills Road, Australian Capital Territory, Acton, 2601, Australia.
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15
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Innate Immunity in Age-Related Macular Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1256:121-141. [PMID: 33848000 DOI: 10.1007/978-3-030-66014-7_5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multiple lines of investigation have demonstrated that inflammation plays significant roles in etiology of age-related macular degeneration (AMD). Although interventional trials in AMD therapy targeting inflammatory pathways have been conducted, they have not yet been successful and a detailed understanding as to why some have failed is still elusive. One limitation is the relative dearth of information on how immune cells interact with retinal cells to generate AMD phenotypes at each disease stage. Here, we summarize current research evidence and hypotheses regarding potential pathogenic roles of innate immune cells in the eye, which include resident retinal microglia, macrophages derived from infiltrating systemic monocytes, and macrophages resident in the choroid. We relate recent findings regarding the physiology, function, and cellular interactions involving innate immune cells in the retina and choroid to AMD-related processes, including: (1) drusen formation and regression, (2) the onset and spread of degeneration in late atrophic AMD, and (3) the initiation, growth, and exudation of neovascular vessels in late "wet" AMD. Understanding how innate immune cells contribute to specific AMD phenotypes can assist in generating a comprehensive view on the inflammatory etiology of AMD and aid in identifying anti-inflammatory therapeutic strategies and selecting appropriate clinical outcomes for the planned interventions.
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16
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Stravalaci M, Davi F, Parente R, Gobbi M, Bottazzi B, Mantovani A, Day AJ, Clark SJ, Romano MR, Inforzato A. Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration. Front Pharmacol 2020; 11:591908. [PMID: 33324220 PMCID: PMC7725797 DOI: 10.3389/fphar.2020.591908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/28/2020] [Indexed: 12/28/2022] Open
Abstract
Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.
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Affiliation(s)
- Matteo Stravalaci
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy
| | - Francesca Davi
- Humanitas Clinical and Research Center IRCCS, Milan, Italy
| | | | - Marco Gobbi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | - Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Anthony J Day
- Wellcome Trust Centre for Cell-Matrix Research and Lydia Becker Institute of Immunology and Inflammation, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Simon J Clark
- Universitäts-Augenklinik Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.,The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Mario R Romano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Eye Center, Humanitas Gavazzeni-Castelli, Bergamo, Italy
| | - Antonio Inforzato
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy
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17
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Jiao H, Provis JM, Natoli R, Rutar M. Ablation of C3 modulates macrophage reactivity in the outer retina during photo-oxidative damage. Mol Vis 2020; 26:679-690. [PMID: 33088172 PMCID: PMC7553722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 10/08/2020] [Indexed: 11/14/2022] Open
Abstract
Purpose Dysregulation of the complement cascade contributes to a variety of retinal dystrophies, including age-related macular degeneration (AMD). The central component of complement, C3, is expressed in abundance by macrophages in the outer retina, and its ablation suppresses photoreceptor death in experimental photo-oxidative damage. Whether this also influences macrophage reactivity in this model system, however, is unknown. We investigate the effect of C3 ablation on macrophage activity and phagocytosis by outer retinal macrophages during photo-oxidative damage. Methods Age-matched C3 knockout (KO) mice and wild-type (WT) C57/Bl6 mice were subjected to photo-oxidative damage. Measurements of the outer nuclear layer (ONL) thickness and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess pathology and photoreceptor apoptosis, respectively. Macrophage abundance and phagocytosis were assessed with immunolabeling for pan-macrophage and phagocytic markers, in conjunction with TUNEL staining in cohorts of C3 KO and WT mice. Results The C3 KO mice exhibited protection against photoreceptor cell death following photo-oxidative damage, which was associated with a reduction in immunoreactivity for the stress-related factor GFAP. In conjunction, there was a reduction in IBA1-positive macrophages in the outer retina compared to the WT mice and a decrease in the number of CD68-positive cells in the outer nuclear layer and the subretinal space. In addition, the engulfment of TUNEL-positive and -negative photoreceptors by macrophages was significantly lower in the C3 KO mice cohort following photo-oxidative damage compared to the WT cohort. Conclusions The results show that the absence of C3 mitigates the phagocytosis of photoreceptors by macrophages in the outer retina, and the net impact of C3 depletion is neuroprotective in the context of photo-oxidative damage. These data improve our understanding of the impact of C3 inhibition in subretinal inflammation and inform the development of treatments for targeting complement activation in diseases such as AMD.
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Affiliation(s)
- Haihan Jiao
- Department of Optometry and Vision Science, University of Melbourne, Victoria, Australia,The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Jan M. Provis
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia,The Australian National University Medical School, Acton, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia,The Australian National University Medical School, Acton, Australia
| | - Matt Rutar
- Department of Anatomy and Neuroscience, University of Melbourne, Victoria, Australia
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18
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Shahulhameed S, Vishwakarma S, Chhablani J, Tyagi M, Pappuru RR, Jakati S, Chakrabarti S, Kaur I. A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy. Front Immunol 2020; 11:154. [PMID: 32117292 PMCID: PMC7026189 DOI: 10.3389/fimmu.2020.00154] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/21/2020] [Indexed: 01/15/2023] Open
Abstract
The complement system plays a crucial role in retinal homeostasis. While the proteomic analysis of ocular tissues in diabetic retinopathy (DR) has shown the deposition of complement proteins, their exact role in the pathogenesis of DR is yet unclear. We performed a detailed investigation of the role of the complement system by evaluating the levels of major complement proteins including C3, C1q, C4b, Complement Factor B (CFB), and Complement Factor H (CFH) and their activated fragments from both the classical and alternative pathways in vitreous humor and serum samples from proliferative DR (PDR) patients and controls. Further, the expressions of complements and several other key pro- and anti-angiogenic genes in the serum and vitreous humor were analyzed in the blood samples of PDR and non-PDR (NPDR) patients along with controls without diabetes. We also assessed the pro-inflammatory cytokines and matrix metalloproteinases in the vitreous humor samples. There was a significant increase in C3 and its activated fragment C3bα' (110 kDa) along with a corresponding upregulation of CFH in the vitreous of PDR patients, which confirmed the increased activation of the alternative complement pathway in PDR. Likewise, a significant upregulation of angiogenic genes and downregulation of anti-angiogenic genes was seen in PDR and NPDR cases. Increased MMP9 activity and upregulation of inflammatory markers IL8 and sPECAM with a downregulation of anti-inflammatory marker IL-10 in PDR vitreous indicated the possible involvement of microglia in DR pathogenesis. Further, a significantly high C3 deposition in the capillary wall along with thickening of basement membranes and co-localization of CFH expression with CD11b+ve activated microglial cells in diabetic retina suggested microglia as a source of CFH in diabetic retina. The increased CFH levels could be a feedback mechanism for arresting excessive complement activation in DR eyes. A gradual increase of CFH and CD11b expression in retina with early to late changes in epiretinal membranes of DR patients indicated a major role for the alternative complement pathway in disease progression.
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Affiliation(s)
- Shahna Shahulhameed
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
| | - Sushma Vishwakarma
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
| | - Jay Chhablani
- Smt. Kanuri Santhamma Center for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.,Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Mudit Tyagi
- Smt. Kanuri Santhamma Center for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India
| | - Rajeev R Pappuru
- Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Saumya Jakati
- Ophthalmic Pathology Laboratory, LV Prasad Eye Institute, Hyderabad, India
| | | | - Inderjeet Kaur
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
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19
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Wooff Y, Fernando N, Wong JHC, Dietrich C, Aggio-Bruce R, Chu-Tan JA, Robertson AAB, Doyle SL, Man SM, Natoli R. Caspase-1-dependent inflammasomes mediate photoreceptor cell death in photo-oxidative damage-induced retinal degeneration. Sci Rep 2020; 10:2263. [PMID: 32041990 PMCID: PMC7010818 DOI: 10.1038/s41598-020-58849-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 01/06/2020] [Indexed: 01/14/2023] Open
Abstract
Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11-/- mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3-/- mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2-/-, Nlrc4-/-, Asc-/-, and Casp11-/- mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations.
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Affiliation(s)
- Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
- The ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Josephine H C Wong
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Catherine Dietrich
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Joshua A Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
- The ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Avril A B Robertson
- School of Chemistry and Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Sarah L Doyle
- Department of Clinical Medicine, School of Medicine, Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
- The National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
| | - Si Ming Man
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
- The ANU Medical School, The Australian National University, Canberra, ACT, Australia.
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20
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Wadhwa M, Prabhakar A, Anand JP, Ray K, Prasad D, Kumar B, Panjwani U. Complement activation sustains neuroinflammation and deteriorates adult neurogenesis and spatial memory impairment in rat hippocampus following sleep deprivation. Brain Behav Immun 2019; 82:129-144. [PMID: 31408672 DOI: 10.1016/j.bbi.2019.08.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/07/2019] [Accepted: 08/07/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND An association between neuroinflammation, reduced adult neurogenesis, and cognitive impairment has been established in sleep deprivation (SD). Complement receptors are expressed on neuronal and glial cells, thus, regulate the neuroinflammation, neurogenesis and learning/memory. However, understanding of the effect of SD on the brain-immune system interaction associated with cognitive dysfunction and its mechanisms is obscure. We hypothesized that complement activation induced changes in inflammatory and neurogenesis related proteins might be involved in the cognitive impairment during SD. METHODOLOGY Adult male Sprague Dawley rats were used. Rats were sleep deprived for 48 h using a novel automated SD apparatus. Dosage of BrdU (50 mg/kg/day, i.p. in 0.07 N NaOH), complement C3a receptor antagonist (C3aRA; SB290157; 1 mg/kg/day, i.p.) in 1.16% v/v PBS and complement C5a receptor antagonist (C5aRA; W-54011; 1 mg/kg/day, i.p.) in normal saline were used. Rats were subjected to spatial memory evaluation following SD. Hippocampal tissue was collected for biochemical, molecular, and immunohistochemical studies. T-test and ANOVA were used for the statistical analysis. RESULTS An up-regulation in the levels of complement components (C3, C5, C3a, C5a) and receptors (C3aR and C5aR) in hippocampus, displayed the complement activation during SD. Selective antagonism of C3aR/C5aR improved the spatial memory performance of sleep-deprived rats. C3aR antagonist (C3aRA) or C5aR antagonist (C5aRA) treatment inhibited the gliosis, maintained inflammatory cytokines balance in hippocampus during SD. Complement C3aR/C5aR antagonism improved hippocampal adult neurogenesis via up-regulating the BDNF level following SD. Administration of C3aRA and C5aRA significantly maintained synaptic homeostasis in hippocampus after SD. Gene expression analysis showed down-regulation in the mRNA levels of signal transduction pathways (Notch and Wnt), differentiation and axogenous proteins, which were found to be improved after C3aRA/C5aRA treatment. These findings were validated at protein and cellular level. Changes in the corticosterone level and ATP-adenosine-NO pathway were established as the key mechanisms underlying complement activation mediated consequences of SD. CONCLUSION Our study suggests complement (C3a-C3aR and C5a-C5aR) activation as the novel mechanism underlying spatial memory impairment via promoting neuroinflammation and adult neurogenesis decline in hippocampus during SD, thereby, complement (C3aR/C5aR) antagonist may serve as the novel therapeutics to improve the SD mediated consequences.
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Affiliation(s)
- Meetu Wadhwa
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Amit Prabhakar
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Jag Pravesh Anand
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Koushik Ray
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Dipti Prasad
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Bhuvnesh Kumar
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India
| | - Usha Panjwani
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence Research and Development Organization (DRDO), Lucknow Road, Timarpur, Delhi, India.
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Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology 2019; 127:186-195. [PMID: 31474439 DOI: 10.1016/j.ophtha.2019.07.011] [Citation(s) in RCA: 371] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 06/27/2019] [Accepted: 07/09/2019] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS Two hundred forty-six patients with GA. METHODS Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.
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22
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Silverman SM, Ma W, Wang X, Zhao L, Wong WT. C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa. J Exp Med 2019; 216:1925-1943. [PMID: 31209071 PMCID: PMC6683998 DOI: 10.1084/jem.20190009] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 03/04/2019] [Accepted: 05/09/2019] [Indexed: 12/24/2022] Open
Abstract
Silverman et al. demonstrate that complement activation features prominently in retinitis pigmentosa in close association with activated microglia. This response mediates adaptive neuroprotection for photoreceptors by facilitating a C3-CR3–dependent clearance of apoptotic photoreceptors by microglial phagocytosis. Complement activation has been implicated as contributing to neurodegeneration in retinal and brain pathologies, but its role in retinitis pigmentosa (RP), an inherited and largely incurable photoreceptor degenerative disease, is unclear. We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia–photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP. These homeostatic neuroinflammatory mechanisms are relevant to the design and interpretation of immunomodulatory therapeutic approaches to retinal degenerative disease.
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Affiliation(s)
- Sean M Silverman
- Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Wenxin Ma
- Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Xu Wang
- Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Lian Zhao
- Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Wai T Wong
- Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD
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23
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Fernando N, Wooff Y, Aggio-Bruce R, Chu-Tan JA, Jiao H, Dietrich C, Rutar M, Rooke M, Menon D, Eells JT, Valter K, Board PG, Provis J, Natoli R. Photoreceptor Survival Is Regulated by GSTO1-1 in the Degenerating Retina. Invest Ophthalmol Vis Sci 2019; 59:4362-4374. [PMID: 30193308 DOI: 10.1167/iovs.18-24627] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Glutathione-S-transferase omega 1-1 (GSTO1-1) is a cytosolic glutathione transferase enzyme, involved in glutathionylation, toll-like receptor signaling, and calcium channel regulation. GSTO1-1 dysregulation has been implicated in oxidative stress and inflammation, and contributes to the pathogenesis of several diseases and neurological disorders; however, its role in retinal degenerations is unknown. The aim of this study was to investigate the role of GSTO1-1 in modulating oxidative stress and consequent inflammation in the normal and degenerating retina. Methods The role of GSTO1-1 in retinal degenerations was explored by using Gsto1-/- mice in a model of retinal degeneration. The expression and localization of GSTO1-1 were investigated with immunohistochemistry and Western blot. Changes in the expression of inflammatory (Ccl2, Il-1β, and C3) and oxidative stress (Nox1, Sod2, Gpx3, Hmox1, Nrf2, and Nqo1) genes were investigated via quantitative real-time polymerase chain reaction. Retinal function in Gsto1-/- mice was investigated by using electroretinography. Results GSTO1-1 was localized to the inner segment of cone photoreceptors in the retina. Gsto1-/- photo-oxidative damage (PD) mice had decreased photoreceptor cell death as well as decreased expression of inflammatory (Ccl2, Il-1β, and C3) markers and oxidative stress marker Nqo1. Further, retinal function in the Gsto1-/- PD mice was increased as compared to wild-type PD mice. Conclusions These results indicate that GSTO1-1 is required for inflammatory-mediated photoreceptor death in retinal degenerations. Targeting GSTO1-1 may be a useful strategy to reduce oxidative stress and inflammation and ameliorate photoreceptor loss, slowing the progression of retinal degenerations.
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Affiliation(s)
- Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,The ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Joshua A Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Haihan Jiao
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Catherine Dietrich
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Melissa Rooke
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Deepthi Menon
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Janis T Eells
- Department of Biomedical Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,The ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Philip G Board
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,The ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,The ANU Medical School, The Australian National University, Canberra, Australian Capital Territory, Australia
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24
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Bell K, Und Hohenstein-Blaul NVT, Teister J, Grus F. Modulation of the Immune System for the Treatment of Glaucoma. Curr Neuropharmacol 2018; 16:942-958. [PMID: 28730968 PMCID: PMC6120111 DOI: 10.2174/1570159x15666170720094529] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/17/2017] [Accepted: 07/18/2017] [Indexed: 12/20/2022] Open
Abstract
Background: At present intraocular pressure (IOP) lowering therapies are the only approach to treat glaucoma. Neuroprotective strategies to protect the retinal ganglion cells (RGC) from apoptosis are lacking to date. Substantial amount of research concerning the role of the immune system in glaucoma has been performed in the recent years. This review aims to analyse changes found in the peripheral immune system, as well as selected local changes of retina immune cells in the glaucomatous retina. Methods: By dividing the immune system into the innate and the adaptive immune system, a systematic literature research was performed to find recent approaches concerning the modulation of the immune system in the context of glaucoma. Also ClinicalTrials.gov was assessed to identify studies with a translational context. Results: We found that some aspects of the immune system, such as changes in antibody levels, changes in toll like receptor signalling, T cells and retinal microglial cells, experience more research activity than other areas such as changes in dendritic cells or macrophages. Briefly, results from clinical studies revealed altered immunoreactivities against retinal and optic nerve antigens in sera and aqueous humor of glaucoma patients and point toward an autoimmune involvement in glaucomatous neurodegeneration and RGC death. IgG accumulations along with plasma cells were found localised in human glaucomatous retinae in a pro-inflammatory environment possibly maintained by microglia. Animal studies show that antibodies (e.g. anti- heat shock protein 60 and anti-myelin basic protein) elevated in glaucoma patients provoke autoaggressive RGC loss and are associated with IgG depositions and increased microglial cells. Also, studies addressing changes in T lymphocytes, macrophages but also local immune responses in the retina have been performed and also hold promising results. Conclusions: This recapitulation of recent literature demonstrates that the immune system definitely plays a role in the pathogenesis of glaucoma. Multiple changes in the peripheral innate as well as adaptive immune system have been detected and give room for further research concerning valuable therapeutic targets. We conclude that there still is a great need to bring together the results derived from basic research analysing different aspects of the immune system in glaucoma to understand the immune context of the disease. Furthermore local immune changes in the retina of glaucoma patients still leave room for further therapeutic targets
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Affiliation(s)
- Katharina Bell
- Experimental and Translational Ophthalmology Mainz, Department of Ophthalmology, Medical Center of the Johannes Gutenberg University Mainz; Langenbeckstrasse 1, 55101 Mainz, Germany
| | - Nadine von Thun Und Hohenstein-Blaul
- Experimental and Translational Ophthalmology Mainz, Department of Ophthalmology, Medical Center of the Johannes Gutenberg University Mainz; Langenbeckstrasse 1, 55101 Mainz, Germany
| | - Julia Teister
- Experimental and Translational Ophthalmology Mainz, Department of Ophthalmology, Medical Center of the Johannes Gutenberg University Mainz; Langenbeckstrasse 1, 55101 Mainz, Germany
| | - Franz Grus
- Experimental and Translational Ophthalmology Mainz, Department of Ophthalmology, Medical Center of the Johannes Gutenberg University Mainz; Langenbeckstrasse 1, 55101 Mainz, Germany
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25
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Jiao H, Rutar M, Fernando N, Yednock T, Sankaranarayanan S, Aggio-Bruce R, Provis J, Natoli R. Subretinal macrophages produce classical complement activator C1q leading to the progression of focal retinal degeneration. Mol Neurodegener 2018; 13:45. [PMID: 30126455 PMCID: PMC6102844 DOI: 10.1186/s13024-018-0278-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 08/13/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The role of the alternative complement pathway and its mediation by retinal microglia and macrophages, is well-established in the pathogenesis of Age-Related Macular Degeneration (AMD). However, the contribution of the classical complement pathway towards the progression of retinal degenerations is not fully understood, including the role of complement component 1q (C1q) as a critical activator molecule of the classical pathway. Here, we investigated the contribution of C1q to progressive photoreceptor loss and neuroinflammation in retinal degenerations. METHODS Wild-type (WT), C1qa knockout (C1qa-/-) and mice treated with a C1q inhibitor (ANX-M1; Annexon Biosciences), were exposed to photo-oxidative damage (PD) and were observed for progressive lesion development. Retinal function was assessed by electroretinography, followed by histological analyses to assess photoreceptor degeneration. Retinal inflammation was investigated through complement activation, macrophage recruitment and inflammasome expression using western blotting, qPCR and immunofluorescence. C1q was localised in human AMD donor retinas using immunohistochemistry. RESULTS PD mice had increased levels of C1qa which correlated with increasing photoreceptor cell death and macrophage recruitment. C1qa-/- mice did not show any differences in photoreceptor loss or inflammation at 7 days compared to WT, however at 14 days after the onset of damage, C1qa-/- retinas displayed less photoreceptor cell death, reduced microglia/macrophage recruitment to the photoreceptor lesion, and higher visual function. C1qa-/- mice displayed reduced inflammasome and IL-1β expression in microglia and macrophages in the degenerating retina. Retinal neutralisation of C1q, using an intravitreally-delivered anti-C1q antibody, reduced the progression of retinal degeneration following PD, while systemic delivery had no effect. Finally, retinal C1q was found to be expressed by subretinal microglia/macrophages located in the outer retina of early AMD donor eyes, and in mouse PD retinas. CONCLUSIONS Our data implicate subretinal macrophages, C1q and the classical pathway in progressive retinal degeneration. We demonstrate a role of local C1q produced by microglia/macrophages as an instigator of inflammasome activation and inflammation. Crucially, we have shown that retinal C1q neutralisation during disease progression may slow retinal atrophy, providing a novel strategy for the treatment of complement-mediated retinal degenerations including AMD.
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Affiliation(s)
- Haihan Jiao
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.,Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia
| | - Ted Yednock
- Annexon Biosciences, South San Francisco, CA, USA
| | | | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.,ANU Medical School, The Australian National University, ACT, Canberra, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia. .,ANU Medical School, The Australian National University, ACT, Canberra, Australia.
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26
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Chu-Tan JA, Rutar M, Saxena K, Aggio-Bruce R, Essex RW, Valter K, Jiao H, Fernando N, Wooff Y, Madigan MC, Provis J, Natoli R. MicroRNA-124 Dysregulation is Associated With Retinal Inflammation and Photoreceptor Death in the Degenerating Retina. Invest Ophthalmol Vis Sci 2018; 59:4094-4105. [PMID: 30098196 PMCID: PMC11647551 DOI: 10.1167/iovs.18-24623] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 06/27/2018] [Indexed: 11/24/2022] Open
Abstract
Purpose We sought to determine the role and retinal cellular location of microRNA-124 (miR-124) in a neuroinflammatory model of retinal degeneration. Further, we explored the anti-inflammatory relationship of miR-124 with a predicted messenger RNA (mRNA) binding partner, chemokine (C-C motif) ligand 2 (Ccl2), which is crucially involved in inflammatory cell recruitment in the damaged retina. Methods Human AMD donor eyes and photo-oxidative damaged (PD) mice were labeled for miR-124 expression using in situ hybridization. PDGFRa-cre RFP mice were used for Müller cell isolation from whole retinas. MIO-M1 immortalized cells and rat primary Müller cells were used for in vitro analysis of miR-124 expression and its relationship with Ccl2. Therapeutic efficacy was tested with intravitreal administration of miR-124 mimic in mice, with electroretinography used to determine retinal function. IBA1 immunohistochemistry and photoreceptor row counts were used for assessment of inflammation and cell death. Results MiR-124 expression was correlated with progressive retinal damage, inflammation, and cell death in human AMD and PD mice. In addition, miR-124 expression was inversely correlated to Ccl2 expression in mice following PD. MiR-124 was localized to both neuronal-like photoreceptors and glial (Müller) cells in the retina, with a redistribution from neurons to glia occurring as a consequence of PD. Finally, intravitreal administration of miR-124 mimics decreased retinal inflammation and photoreceptor cell death, and improved retinal function. Conclusions This study has provided an understanding of the mechanism behind miR-124 in the degenerating retina and demonstrates the usefulness of miR-124 mimics for the modulation of retinal degenerations.
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Affiliation(s)
- Joshua A. Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Kartik Saxena
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Rohan W. Essex
- Academic Unit of Ophthalmology, The Australian National University, Canberra, Australia
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
- The Australian National University Medical School, Acton, Australia
| | - Haihan Jiao
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
| | - Michele C. Madigan
- Save Sight Institute, Discipline of Clinical Ophthalmology, The University of Sydney, Sydney, Australia
- School of Optometry and Vision Science, The University of New South Wales, Kensington, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
- The Australian National University Medical School, Acton, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Acton, Australia
- The Australian National University Medical School, Acton, Australia
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Rathnasamy G, Foulds WS, Ling EA, Kaur C. Retinal microglia - A key player in healthy and diseased retina. Prog Neurobiol 2018; 173:18-40. [PMID: 29864456 DOI: 10.1016/j.pneurobio.2018.05.006] [Citation(s) in RCA: 161] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/09/2018] [Accepted: 05/29/2018] [Indexed: 01/04/2023]
Abstract
Microglia, the resident immune cells of the brain and retina, are constantly engaged in the surveillance of their surrounding neural tissue. During embryonic development they infiltrate the retinal tissues and participate in the phagocytosis of redundant neurons. The contribution of microglia in maintaining the purposeful and functional histo-architecture of the adult retina is indispensable. Within the retinal microenvironment, robust microglial activation is elicited by subtle changes caused by extrinsic and intrinsic factors. When there is a disturbance in the cell-cell communication between microglia and other retinal cells, for example in retinal injury, the activated microglia can manifest actions that can be detrimental. This is evidenced by activated microglia secreting inflammatory mediators that can further aggravate the retinal injury. Microglial activation as a harbinger of a variety of retinal diseases is well documented by many studies. In addition, a change in the microglial phenotype which may be associated with aging, may predispose the retina to age-related diseases. In light of the above, the focus of this review is to highlight the role played by microglia in the healthy and diseased retina, based on findings of our own work and from that of others.
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Affiliation(s)
- Gurugirijha Rathnasamy
- Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, 117594, Singapore; Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53706, United States
| | - Wallace S Foulds
- Singapore Eye Research Institute Level 6, The Academia, Discovery Tower, 20 College Road, 169856, Singapore; University of Glasgow, Glasgow, Scotland, G12 8QQ, United Kingdom
| | - Eng-Ang Ling
- Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, 117594, Singapore
| | - Charanjit Kaur
- Department of Anatomy, Yong Loo Lin School of Medicine, Blk MD10, 4 Medical Drive, National University of Singapore, 117594, Singapore.
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Fernando N, Natoli R, Racic T, Wooff Y, Provis J, Valter K. The use of the vaccinia virus complement control protein (VCP) in the rat retina. PLoS One 2018; 13:e0193740. [PMID: 29534078 PMCID: PMC5849281 DOI: 10.1371/journal.pone.0193740] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 02/16/2018] [Indexed: 01/11/2023] Open
Abstract
The complement system is highly implicated in both the prevalence and progression of Age-Related Macular Degeneration (AMD). Complement system inhibitors therefore have potential therapeutic value in managing excessive activation of the complement pathways in retinal degenerations. The vaccinia virus complement control protein (VCP) has been shown to be effective as a complement inhibitor in neuroinflammatory models including traumatic brain injury and spinal cord injury. We aimed to investigate the potential of VCP as a therapeutic molecule for retinal degenerations. In this study, we investigated the effect, localisation and delivery of VCP to the rodent retina. Complement inhibition activity of VCP was tested using a hemolytic assay. Photoreceptor cell death, inflammation and retinal stress were assayed to determine if any retinal toxicity was induced by an intravitreal injection of VCP. The effect of VCP was investigated in a model of photo-oxidative retinal degeneration. Localisation of VCP after injection was determined using a fluorescein-tagged form of VCP, as well as immunohistochemistry. Finally, a copolymer resin (Elvax) was trialled for the slow-release delivery of VCP to the retina. We found that a dose equivalent to 20μg VCP when intravitreally injected into the rat eye did not cause any photoreceptor cell death or immune cell recruitment, but led to an increase in GFAP. In photo-oxidative damaged retinas, there were no differences in photoreceptor loss, retinal stress (Gfap) and inflammation (Ccl2 and C3) between VCP and saline-injected groups; however, Jun expression was reduced in VCP-treated retinas. After VCP was injected into the eye, it was taken up in all layers of the retina but was cleared within 1-3 hours of delivery. This study indicates that a method to sustain the delivery of VCP to the retina is necessary to further investigate the effect of VCP as a complement inhibitor for retinal degenerations.
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Affiliation(s)
- Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Tanja Racic
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
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Natoli R, Fernando N, Dahlenburg T, Jiao H, Aggio-Bruce R, Barnett NL, Chao de la Barca JM, Tcherkez G, Reynier P, Fang J, Chu-Tan JA, Valter K, Provis J, Rutar M. Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment. Mol Vis 2018; 24:201-217. [PMID: 29527116 PMCID: PMC5842320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 03/05/2018] [Indexed: 11/03/2022] Open
Abstract
Purpose Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Methods Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Results Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. Conclusions The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.
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Affiliation(s)
- Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Tess Dahlenburg
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Haihan Jiao
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Nigel L. Barnett
- Queensland Eye Institute, South Brisbane, Queensland, Australia
- The University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
| | | | - Guillaume Tcherkez
- Research School of Biology, The Australian National University, Canberra, Australia
| | - Pascal Reynier
- PREMMi / Pôle de Recherche et d’Enseignement en Médecine Mitochondriale, Institut MITOVASC, CNRS 6214, INSERM U1083, Université d'Angers, 49933 Angers, France
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire, 49933 Angers, France
| | - Johnny Fang
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Joshua A. Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- ANU Medical School, The Australian National University, Canberra, Australia
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Canberra, Australia
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Madeira MH, Rashid K, Ambrósio AF, Santiago AR, Langmann T. Blockade of microglial adenosine A2A receptor impacts inflammatory mechanisms, reduces ARPE-19 cell dysfunction and prevents photoreceptor loss in vitro. Sci Rep 2018; 8:2272. [PMID: 29396515 PMCID: PMC5797099 DOI: 10.1038/s41598-018-20733-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 01/22/2018] [Indexed: 01/22/2023] Open
Abstract
Age-related macular degeneration (AMD) is characterized by pathological changes in the retinal pigment epithelium (RPE) and loss of photoreceptors. Growing evidence has demonstrated that reactive microglial cells trigger RPE dysfunction and loss of photoreceptors, and inflammasome pathways and complement activation contribute to AMD pathogenesis. We and others have previously shown that adenosine A2A receptor (A2AR) blockade prevents microglia-mediated neuroinflammatory processes and mediates protection to the retina. However, it is still unknown whether blocking A2AR in microglia protects against the pathological features of AMD. Herein, we show that an A2AR antagonist, SCH58261, prevents the upregulation of the expression of pro-inflammatory mediators and the alterations in the complement system triggered by an inflammatory challenge in human microglial cells. Furthermore, blockade of A2AR in microglia decreases the inflammatory response, as well as complement and inflammasome activation, in ARPE-19 cells exposed to conditioned medium of activated microglia. Finally, we also show that blocking A2AR in human microglia increases the clearance of apoptotic photoreceptors. This study opens the possibility of using selective A2AR antagonists in therapy for AMD, by modulating the interplay between microglia, RPE and photoreceptors.
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Affiliation(s)
- M H Madeira
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal.,Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - K Rashid
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - A F Ambrósio
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal.,Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal
| | - A R Santiago
- Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,CNC.IBILI Consortium, University of Coimbra, Coimbra, Portugal.,Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, Portugal
| | - T Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
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31
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Rathi S, Jalali S, Patnaik S, Shahulhameed S, Musada GR, Balakrishnan D, Rani PK, Kekunnaya R, Chhablani PP, Swain S, Giri L, Chakrabarti S, Kaur I. Abnormal Complement Activation and Inflammation in the Pathogenesis of Retinopathy of Prematurity. Front Immunol 2017; 8:1868. [PMID: 29312345 PMCID: PMC5743907 DOI: 10.3389/fimmu.2017.01868] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 12/08/2017] [Indexed: 01/20/2023] Open
Abstract
Retinopathy of prematurity (ROP) is a neurovascular complication in preterm babies, leading to severe visual impairment, but the underlying mechanisms are yet unclear. The present study aimed at unraveling the molecular mechanisms underlying the pathogenesis of ROP. A comprehensive screening of candidate genes in preterms with ROP (n = 189) and no-ROP (n = 167) was undertaken to identify variants conferring disease susceptibility. Allele and genotype frequencies, linkage disequilibrium and haplotypes were analyzed to identify the ROP-associated variants. Variants in CFH (p = 2.94 × 10−7), CFB (p = 1.71 × 10−5), FBLN5 (p = 9.2 × 10−4), CETP (p = 2.99 × 10−5), and CXCR4 (p = 1.32 × 10−8) genes exhibited significant associations with ROP. Further, a quantitative assessment of 27 candidate proteins and cytokines in the vitreous and tear samples of babies with severe ROP (n = 30) and congenital cataract (n = 30) was undertaken by multiplex bead arrays and further validated by western blotting and zymography. Significant elevation and activation of MMP9 (p = 0.038), CFH (p = 2.24 × 10−5), C3 (p = 0.05), C4 (p = 0.001), IL-1ra (p = 0.0019), vascular endothelial growth factor (VEGF) (p = 0.0027), and G-CSF (p = 0.0099) proteins were observed in the vitreous of ROP babies suggesting an increased inflammation under hypoxic condition. Along with inflammatory markers, activated macrophage/microglia were also detected in the vitreous of ROP babies that secreted complement component C3, VEGF, IL-1ra, and MMP-9 under hypoxic stress in a cell culture model. Increased expression of the inflammatory markers like the IL-1ra (p = 0.014), MMP2 (p = 0.0085), and MMP-9 (p = 0.03) in the tears of babies at different stages of ROP further demonstrated their potential role in disease progression. Based on these findings, we conclude that increased complement activation in the retina/vitreous in turn activated microglia leading to increased inflammation. A quantitative assessment of inflammatory markers in tears could help in early prediction of ROP progression and facilitate effective management of the disease, thereby preventing visual impairment.
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Affiliation(s)
- Sonika Rathi
- Prof Brien Holden Eye Research Centre, Hyderabad, India
| | - Subhadra Jalali
- Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, Hyderabad, India
| | | | | | | | - Divya Balakrishnan
- Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, Hyderabad, India
| | - Padmaja K Rani
- Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, Hyderabad, India
| | - Ramesh Kekunnaya
- Jasti V Ramanamma Children's Eye Care Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Preeti Patil Chhablani
- Jasti V Ramanamma Children's Eye Care Centre, L V Prasad Eye Institute, Hyderabad, India
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32
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Natoli R, Fernando N, Madigan M, Chu-Tan JA, Valter K, Provis J, Rutar M. Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration. Mol Neurodegener 2017; 12:31. [PMID: 28438165 PMCID: PMC5404662 DOI: 10.1186/s13024-017-0175-y] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/14/2017] [Indexed: 01/10/2023] Open
Abstract
Background Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. Methods Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. Results Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo. Conclusions IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.
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Affiliation(s)
- Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Michele Madigan
- Save Sight Institute, Discipline of Clinical Ophthalmology, The University of Sydney, Sydney, NSW, Australia.,School of Optometry and Vision Science, The University of New South Wales, Kensington, NSW, Australia
| | - Joshua A Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia. .,ANU Medical School, The Australian National University, Canberra, ACT, Australia.
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,The University of Melbourne, Parkville, VIC, Australia
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33
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Del Amo EM, Rimpelä AK, Heikkinen E, Kari OK, Ramsay E, Lajunen T, Schmitt M, Pelkonen L, Bhattacharya M, Richardson D, Subrizi A, Turunen T, Reinisalo M, Itkonen J, Toropainen E, Casteleijn M, Kidron H, Antopolsky M, Vellonen KS, Ruponen M, Urtti A. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res 2016; 57:134-185. [PMID: 28028001 DOI: 10.1016/j.preteyeres.2016.12.001] [Citation(s) in RCA: 451] [Impact Index Per Article: 50.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 11/25/2016] [Accepted: 12/01/2016] [Indexed: 12/14/2022]
Abstract
Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.
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Affiliation(s)
- Eva M Del Amo
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Anna-Kaisa Rimpelä
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Emma Heikkinen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Otto K Kari
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Eva Ramsay
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Tatu Lajunen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Mechthild Schmitt
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Laura Pelkonen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Madhushree Bhattacharya
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Dominique Richardson
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Astrid Subrizi
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Tiina Turunen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Mika Reinisalo
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Jaakko Itkonen
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Elisa Toropainen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Marco Casteleijn
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Heidi Kidron
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | - Maxim Antopolsky
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland
| | | | - Marika Ruponen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Arto Urtti
- Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland; School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
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34
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Schäfer N, Grosche A, Reinders J, Hauck SM, Pouw RB, Kuijpers TW, Wouters D, Ehrenstein B, Enzmann V, Zipfel PF, Skerka C, Pauly D. Complement Regulator FHR-3 Is Elevated either Locally or Systemically in a Selection of Autoimmune Diseases. Front Immunol 2016; 7:542. [PMID: 27965669 PMCID: PMC5124756 DOI: 10.3389/fimmu.2016.00542] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 11/16/2016] [Indexed: 12/30/2022] Open
Abstract
The human complement factor H-related protein-3 (FHR-3) is a soluble regulator of the complement system. Homozygous cfhr3/1 deletion is a genetic risk factor for the autoimmune form of atypical hemolytic-uremic syndrome (aHUS), while also found to be protective in age-related macular degeneration (AMD). The precise function of FHR-3 remains to be fully characterized. We generated four mouse monoclonal antibodies (mAbs) for FHR-3 (RETC) without cross-reactivity to the complement factor H (FH)-family. These antibodies detected FHR-3 from human serum with a mean concentration of 1 μg/mL. FHR-3 levels in patients were significantly increased in sera from systemic lupus erythematosus, rheumatoid arthritis, and polymyalgia rheumatica but remained almost unchanged in samples from AMD or aHUS patients. Moreover, by immunostaining of an aged human donor retina, we discovered a local FHR-3 production by microglia/macrophages. The mAb RETC-2 modulated FHR-3 binding to C3b but not the binding of FHR-3 to heparin. Interestingly, FHR-3 competed with FH for binding C3b and the mAb RETC-2 reduced the interaction of FHR-3 and C3b, resulting in increased FH binding. Our results unveil a previously unknown systemic involvement of FHR-3 in rheumatoid diseases and a putative local role of FHR-3 mediated by microglia/macrophages in the damaged retina. We conclude that the local FHR-3/FH equilibrium in AMD is a potential therapeutic target, which can be modulated by our specific mAb RETC-2.
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Affiliation(s)
- Nicole Schäfer
- Department of Ophthalmology, University Hospital Regensburg , Regensburg , Germany
| | - Antje Grosche
- Institute of Human Genetics, University of Regensburg , Regensburg , Germany
| | - Joerg Reinders
- Institute of Functional Genomics, University of Regensburg , Regensburg , Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH) , Neuherberg , Germany
| | - Richard B Pouw
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands
| | - Taco W Kuijpers
- Department of Pediatric Hematology, Immunology and Infectious Diseases, Academic Medical Center, Emma Children's Hospital, Amsterdam, Netherlands; Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Diana Wouters
- Department of Immunopathology, Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, University of Amsterdam , Amsterdam , Netherlands
| | - Boris Ehrenstein
- Klinik und Poliklinik für Rheumatologie und Klinische Immunologie, Asklepios Klinikum Bad Abbach , Bad Abbach , Germany
| | - Volker Enzmann
- Department of Ophthalmology, Inselspital, University of Bern , Bern , Switzerland
| | - Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; Friedrich Schiller University, Jena, Germany
| | - Christine Skerka
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology , Jena , Germany
| | - Diana Pauly
- Department of Ophthalmology, University Hospital Regensburg , Regensburg , Germany
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Verghese PS, Reed RC, Lihong B, Matas AJ, Kim Y. The clinical implications of the unique glomerular complement deposition pattern in transplant glomerulopathy. J Nephrol 2016; 31:157-164. [PMID: 27848227 DOI: 10.1007/s40620-016-0365-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 11/05/2016] [Indexed: 11/25/2022]
Abstract
The etiology and treatment of transplant glomerulopathy (TG) is not clear. TG is associated with donor-specific antibodies but the lack of C4d deposition in the peritubular capillaries (ptc-C4d) in some cases has caused the role of complement in the pathogenesis of TG to be debated. There is however, little information on C4d deposition in the glomerulus itself. We retrieved random frozen sections from 25 cases with well-established TG by light microscopy (LM) and 25 cases without TG as controls and reviewed the LM and immunofluorescence (nine biopsies were excluded due to inadequate samples). Glomerular complement deposition was assessed in all included biopsies. Glomerular C3d and C4d deposition occurred in a distinct pattern in all TG biopsies: segmental or global double linear staining of the glomerular capillary wall in 23 (100%). This pattern was not present in any NON-TG biopsies. The distinct glomerular complement deposition patterns in all TG cases are suggestive that TG is a proximal complement-mediated process and therapies should focus on proximal complement inhibition.
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Affiliation(s)
- Priya S Verghese
- Division of Pediatric Nephrology, University of Minnesota, Minneapolis, USA.
| | - Robin C Reed
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA
| | - Bu Lihong
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, USA
| | - Youngki Kim
- Division of Pediatric Nephrology, University of Minnesota, Minneapolis, USA
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Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease. J Neurosci 2016; 36:577-89. [PMID: 26758846 DOI: 10.1523/jneurosci.2117-15.2016] [Citation(s) in RCA: 409] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
UNLABELLED Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamics in vitro and amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion of C3aR. We further demonstrate that Aβ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-κB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Aβ activates astroglial NF-κB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Aβ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions. SIGNIFICANCE STATEMENT The complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate β-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease.
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Fernando N, Natoli R, Valter K, Provis J, Rutar M. The broad-spectrum chemokine inhibitor NR58-3.14.3 modulates macrophage-mediated inflammation in the diseased retina. J Neuroinflammation 2016; 13:47. [PMID: 26911327 PMCID: PMC4765229 DOI: 10.1186/s12974-016-0514-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 02/18/2016] [Indexed: 12/20/2022] Open
Abstract
Background The activity of macrophages is implicated in the progression of retinal pathologies such as atrophic age-related macular degeneration (AMD), where they accumulate among the photoreceptor layer and subretinal space. This process is aided by the local expression of chemokines, which furnish these cells with directional cues that augment their migration to areas of retinal injury. While these qualities make chemokines a potential therapeutic target in curtailing damaging retinal inflammation, their wide variety and signalling redundancy pose challenges in broadly modulating their activity. Here, we examine the efficacy of the broad-spectrum chemokine inhibitor NR58-3.14.3—a suppressor of Ccl- and Cxcl- chemokine pathways—in suppressing macrophage activity and photoreceptor death, using a light-induced model of outer retinal atrophy and inflammation. Methods Photo-oxidative damage was induced in SD rats via exposure to 1000 lux of light for 24 h, after which animals were euthanized at 0- or 7-day post-exposure time points. Prior to damage, NR58-3.14.3 was injected intravitreally. Retinas were harvested and evaluated for the effect of NR58-3.14.3 on subretinal macrophage accumulation and cytokine expression profile, as well as photoreceptor degeneration. Results We report that intravitreal administration of NR58-3.14.3 reduces the accumulation of macrophages in the outer retina following exposure to light damage, at both 0- and 7-day post-exposure time points. Injection of NR58-3.14.3 also reduced the up-regulation of inflammatory markers including of Il6, Ccl3, and Ccl4 in infiltrating macrophages, which are promoters of their pathogenic activity in the retina. Finally, NR58-3.14.3-injected retinas displayed markedly reduced photoreceptor death following light damage, at both 0 and 7 days post-exposure. Conclusions Our findings indicate that NR58-3.14.3 is effective in inhibiting subretinal macrophage accumulation in light-induced retinal degeneration and illustrate the potential of broad-spectrum chemokine inhibitors as novel therapeutic agents in thwarting retinal inflammation. Although broad-spectrum chemokine inhibitors may not be appropriate for all retinal inflammatory conditions, our results suggest that they may be beneficial for retinal dystrophies in which chemokine expression and subretinal macrophage accumulation are implicated, such as advanced AMD.
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Affiliation(s)
- Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.,ANU Medical School, The Australian National University, Canberra, Australia
| | - Krisztina Valter
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.,ANU Medical School, The Australian National University, Canberra, Australia
| | - Jan Provis
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.,ANU Medical School, The Australian National University, Canberra, Australia
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University, Building 131, Garran Rd, Canberra, ACT, 2601, Australia.
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Kleinman ME, Ambati J. Complement Activation and Inhibition in Retinal Diseases. DEVELOPMENTS IN OPHTHALMOLOGY 2015; 55:46-56. [PMID: 26501209 DOI: 10.1159/000431141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Within the past several decades, a brigade of dedicated researchers from around the world has provided essential insights into the critical niche of immune-mediated inflammation in the pathogenesis of age-related macular degeneration (AMD). Yet, the question has lingered as to whether disease-initiating events are more or less dependent on isolated immune-related responses, unimpeded inflammation, endogenous pathways of age-related cell senescence and oxidative stress, or any of the other numerous molecular derangements that have been identified in the natural history of AMD. There is now an abundant cache of data signifying immune system activation as an impetus in the pathogenesis of this devastating condition. Furthermore, recent rigorous investigations have revealed multiple inciting factors, including several important complement-activating components, thus creating a new array of disease-modulating targets for the research and development of molecular therapeutic interventions. While the precise in vivo effects of complement activation and inhibition in the progression and treatment of AMD remain to be determined, ongoing clinical trials of the first generation of complement-targeted therapeutics are hoped to yield critical data on the contribution of this pathway to the disease process.
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Schraufstatter IU, Khaldoyanidi SK, DiScipio RG. Complement activation in the context of stem cells and tissue repair. World J Stem Cells 2015; 7:1090-1108. [PMID: 26435769 PMCID: PMC4591784 DOI: 10.4252/wjsc.v7.i8.1090] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 07/27/2015] [Indexed: 02/06/2023] Open
Abstract
The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.
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Madeira MH, Boia R, Santos PF, Ambrósio AF, Santiago AR. Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases. Mediators Inflamm 2015; 2015:673090. [PMID: 25873768 PMCID: PMC4385698 DOI: 10.1155/2015/673090] [Citation(s) in RCA: 171] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/16/2014] [Indexed: 12/27/2022] Open
Abstract
Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.
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Affiliation(s)
- Maria H. Madeira
- Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3004-548 Coimbra, Portugal
| | - Raquel Boia
- Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3004-548 Coimbra, Portugal
| | - Paulo F. Santos
- Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3004-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - António F. Ambrósio
- Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3004-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- AIBILI, Coimbra, Portugal
| | - Ana R. Santiago
- Centre of Ophthalmology and Vision Sciences, IBILI, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, 3004-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
- AIBILI, Coimbra, Portugal
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Whitmore SS, Sohn EH, Chirco KR, Drack AV, Stone EM, Tucker BA, Mullins RF. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog Retin Eye Res 2015; 45:1-29. [PMID: 25486088 PMCID: PMC4339497 DOI: 10.1016/j.preteyeres.2014.11.005] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/19/2014] [Accepted: 11/25/2014] [Indexed: 12/24/2022]
Abstract
Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies.
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Affiliation(s)
- S Scott Whitmore
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Elliott H Sohn
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Kathleen R Chirco
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Arlene V Drack
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Edwin M Stone
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Budd A Tucker
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
| | - Robert F Mullins
- The Stephen A. Wynn Institute for Vision Research, The University of Iowa, United States; Department of Ophthalmology and Visual Sciences, The University of Iowa, United States
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Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T. Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res 2014; 45:30-57. [PMID: 25476242 DOI: 10.1016/j.preteyeres.2014.11.004] [Citation(s) in RCA: 412] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 11/20/2014] [Accepted: 11/25/2014] [Indexed: 10/24/2022]
Abstract
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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Affiliation(s)
- Marcus Karlstetter
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Rebecca Scholz
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - Matt Rutar
- The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia
| | - Wai T Wong
- Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jan M Provis
- The John Curtin School of Medical Research, The Australian National University (ANU), Canberra, Australian Capital Territory, Australia
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
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Warwick A, Khandhadia S, Ennis S, Lotery A. Age-Related Macular Degeneration: A Disease of Systemic or Local Complement Dysregulation? J Clin Med 2014; 3:1234-57. [PMID: 26237601 PMCID: PMC4470180 DOI: 10.3390/jcm3041234] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 10/20/2014] [Accepted: 10/22/2014] [Indexed: 01/25/2023] Open
Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in developed countries. The role of complement in the development of AMD is now well-established. While some studies show evidence of complement dysregulation within the eye, others have demonstrated elevated systemic complement activation in association with AMD. It is unclear which one is the primary driver of disease. This has important implications for designing novel complement-based AMD therapies. We present a summary of the current literature and suggest that intraocular rather than systemic modulation of complement may prove more effective.
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Affiliation(s)
- Alasdair Warwick
- Clinical Neurosciences Research Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
| | - Samir Khandhadia
- Eye Unit, University Southampton NHS Trust, Southampton SO16 6YD, UK.
| | - Sarah Ennis
- Genomic Informatics, Human Genetics & Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
| | - Andrew Lotery
- Clinical Neurosciences Research Group, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
- Eye Unit, University Southampton NHS Trust, Southampton SO16 6YD, UK.
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