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Maidana DE, Puente SP, Wang C, Chandra S, Gonzalez-Buendia L, Ilios EP, Kazlauskas A, Vavvas DG. Divergence in photoreceptor cell death and neuroinflammation in transvitreal and transscleral subretinal delivery in mice. J Inflamm (Lond) 2025; 22:5. [PMID: 39920719 PMCID: PMC11806547 DOI: 10.1186/s12950-025-00433-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 01/28/2025] [Indexed: 02/09/2025] Open
Abstract
Subretinal injections provide direct access to photoreceptors and RPE, which is crucial for the delivery of gene therapy and neuroprotective approaches. To access the subretinal space, transvitreal (TV) and transscleral (TS) subretinal injections have been widely used in humans and animal models. In this work, we investigated recent trends and outcomes of utilizing TV and TS subretinal models of retinal detachment (RD). A literature review revealed an increasing utilization of both models over the past two decades, with TS emerging as the predominant model since 2012. Subretinal injection in CX3CR1 + /GFP CCR2 + /RFP mice revealed early inflammatory responses, with TS injections inducing higher infiltration of CD11b + CCR2 + cells compared to TV. Further leukocyte immunophenotyping indicated divergent infiltration patterns, with the TS approach exhibiting higher proportions of neutrophils and macrophages/microglia-like cells, while the TV injections had higher CD45hi CD11b + Ly6G- Ly6C + infiltration. Notably, late-stage analysis demonstrates higher photoreceptor cell death in the TS approach, paralleled by increased subretinal infiltration of CD11b + cells. Both models showed significant reactive gliosis, suggesting comparable late-stage wound healing responses. These findings underscore the utility of these approaches for subretinal delivery, offering insights into their distinctive leukocyte infiltration and late-stage tissue responses.
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Affiliation(s)
- Daniel E Maidana
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Sara Pastor Puente
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
| | - Catherine Wang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
| | - Shivam Chandra
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
| | - Lucia Gonzalez-Buendia
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
- Institute of Ocular Microsurgery (IMO) Miranza Group, Madrid, Spain
| | - Eleftherios Paschalis Ilios
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
- Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA, 02114, USA
| | - Andrius Kazlauskas
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Demetrios G Vavvas
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
- Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA, 02114, USA.
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Scavuzzi BM, Shanmugam S, Yang M, Yao J, Hager H, Kaur B, Jia L, Abcouwer SF, Zacks DN. Remote Preconditioning Provides Protection Against Retinal Cell Death From Retinal Detachment. Invest Ophthalmol Vis Sci 2025; 66:34. [PMID: 39937497 PMCID: PMC11827864 DOI: 10.1167/iovs.66.2.34] [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: 08/23/2024] [Accepted: 01/20/2025] [Indexed: 02/13/2025] Open
Abstract
Purpose Remote preconditioning involves injury to a tissue that results in protection to a subsequent injury in a distal tissue. Here, we investigated the impact of remote preconditioning on retinal detachment (RD) injury, hypothesizing that a previous contralateral RD would protect the fellow retina against inflammation and cell death following its detachment. Methods RD was created in adult C57BL/6J mice with subretinal sodium hyaluronate injection. Preconditioning involved RD in the right eye at 1, 3, 7, or 28 days before left eye detachment, whereas the control group only received RD to the left eye. Retinas were harvested 24 hours post-left eye detachment in both groups. Cell death was assessed using Cell Death Detection ELISA and mRNA expression was evaluated via qRT-PCR. Results Contralateral RD promoted a transient protection against retinal cell death from 1 to 3 days and waned by 7 days compared with control RD retinas with intact fellow retinas. Contralateral RD significantly protected against post-RD cell death (P = 0.0002) and caspase 3 cleavage (P = 0.0449), compared with control RD retinas with intact fellow retinas 1-day post-RD. Detached fellow retinas from the preconditioning group expressed significantly less Tnfa (P = 0.0066), Cxcl10 (P = 0.0099), and Fas (P = 0.0223) mRNAs, compared with the detached retinas of the control group. In contrast, upregulation of type-I-IFN pathway genes, including Irf7 (P = 0.0106) and Ifit1 (P = 0.0740), following RD was higher in the preconditioning group. Conclusions RD in one eye produces a transient remote preconditioning effect that protects the fellow retina against retinal cell death following subsequent RD.
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Affiliation(s)
- Bruna Miglioranza Scavuzzi
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Sumathi Shanmugam
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Mengling Yang
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Jingyu Yao
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Heather Hager
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Bhavneet Kaur
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Lin Jia
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - Steven F. Abcouwer
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
| | - David N. Zacks
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
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Xiao R, Huang X, Gao S, Duan J, Zhang Y, Zhang M. Microglia in retinal diseases: From pathogenesis towards therapeutic strategies. Biochem Pharmacol 2024; 230:116550. [PMID: 39307318 DOI: 10.1016/j.bcp.2024.116550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/21/2024] [Accepted: 09/19/2024] [Indexed: 10/01/2024]
Abstract
Microglia, a widely dispersed cohort of immune cells in the retina, are intricately involved in a diverse range of pivotal biological processes, including inflammation, vascular development, complement activation, antigen presentation, and phagocytosis. Within the retinal milieu, microglia are crucial for the clearance of dead cells and cellular debris, release of anti-inflammatory agents, and orchestration of vascular network remodeling to maintain homeostasis. In addition, microglia are key mediators of neuroinflammation. Triggered by oxidative stress, elevated intraocular pressure, genetic anomalies, and immune dysregulation, microglia release numerous inflammatory cytokines, contributing to the pathogenesis of various retinal disorders. Recent studies on the ontogeny and broad functions of microglia in the retina have elucidated their characteristics during retinal development, homeostasis, and disease. Furthermore, therapeutic strategies that target microglia and their effector cytokines have been developed and shown positive results for some retinal diseases. Therefore, we systematically review the microglial ontogeny in the retina, elucidate their dual roles in retinal homeostasis and disease pathogenesis, and demonstrate microglia-based targeted therapeutic strategies for retinal diseases.
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Affiliation(s)
- Ruihan Xiao
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xi Huang
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Sheng Gao
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jianan Duan
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yun Zhang
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Meixia Zhang
- The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Cao Y, Qiao L, Song Y, Yan Y, Ni Y, Xi H, Chen J, Li S, Liu H. Caspase-1 Inhibition Ameliorates Photoreceptor Damage Following Retinal Detachment by Inhibiting Microglial Pyroptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1924-1937. [PMID: 39032599 DOI: 10.1016/j.ajpath.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 05/31/2024] [Accepted: 06/10/2024] [Indexed: 07/23/2024]
Abstract
Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and play a role in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. VX-765, an inhibitor of caspase-1, may exert neuroprotective effects by targeting microglial pyroptosis in nervous system disease; however, whether it plays a role in RD is uncertain. This study detected and localized pyroptosis to specific cells by immunofluorescence co-staining and flow cytometry in rat RD models. The majority of gasdermin D N-terminal (GSDMD-N)-positive cells exhibited IBA1-positive or P2RY12-positive microglia in the early stage of RD, indicating the pyroptosis of microglia. Administration of VX-765 shifted the microglia phenotype from M1 to M2, inhibited microglial migration toward the outer nuclear layer (ONL) post-RD, and most importantly, inhibited microglial pyroptosis. The thickness of ONL increased with VX-765 administration, and the photoreceptors were more structured and orderly under hematoxylin and eosin staining and transmission electron microscopy, revealing the protective effects of VX-765 on photoreceptors. Overall, this study demonstrated that inflammation induced by pyroptosis of microglia is the early pathological process of RD. VX-765 may serve as a candidate therapeutic approach for the treatment of RD by targeting microglia.
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Affiliation(s)
- Yumei Cao
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Lei Qiao
- Central Laboratory, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China
| | - Yingying Song
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Yuanye Yan
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China
| | - Yewen Ni
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Huiyu Xi
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China
| | - Jiayu Chen
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Suyan Li
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China.
| | - Haiyang Liu
- Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China.
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Kaur B, Miglioranza Scavuzzi B, Yang M, Yao J, Jia L, Abcouwer SF, Zacks DN. ER Stress and Mitochondrial Perturbations Regulate Cell Death in Retinal Detachment: Exploring the Role of HIF1α. Invest Ophthalmol Vis Sci 2024; 65:39. [PMID: 39325470 PMCID: PMC11437674 DOI: 10.1167/iovs.65.11.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2024] Open
Abstract
Purpose Retinal detachment (RD) leads to photoreceptor (PR) hypoxia due to separation from the retinal pigment epithelium (RPE). Hypoxia stabilizes retinal hypoxia-inducible factor 1-alpha (HIF1α), crucial for PR survival during RD. This study explores the regulatory role of HIF1α in PR cell survival pathways during RD. Methods Experimental RD was created in C57BL/6J and HIF1αΔrod mice by injecting 1% hyaluronic acid into the subretinal space. The 661W photoreceptor cells were exposed to hypoxic conditions. Markers of endoplasmic reticulum stress (ERS), mitophagy, and accumulation of polyubiquinated proteins were evaluated using RT-PCR and western blot analyses. Cell death of PR cells was quantified using trypan blue exclusion assay and TUNEL staining. Retinal cell death was assessed using a DNA fragmentation assay. Results In C57BL/6J mice and 661W cells, there were increases in HIF1α protein levels: 2.2-fold after RD (P = 0.04) and threefold after hypoxia (P = 0.057). Both the in vivo and in vitro RD models showed increased protein expression of ERS markers (including BIP, CHOP, and IRE1α), mitophagy markers (Parkin, PINK, and FUNDC1), and polyubiquitinated proteins. In 661W cells, hypoxia resulted in a loss of mitochondrial membrane potential, an increase in mitochondrial reactive oxygen species, and a decrease in intracellular adenosine triphosphate levels. Lack of HIF1α in rods blocked the upregulation of mitophagy markers after RD. Conclusions RD results in the activation of ERS, mitophagy, mitochondrial dysfunction, and accumulation of polyubiquitinated proteins. Results suggest a role for HIF1α in activation of the mitophagy pathway after RD, which may serve to protect the PR cells.
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Affiliation(s)
- Bhavneet Kaur
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - Bruna Miglioranza Scavuzzi
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - Mengling Yang
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - Jingyu Yao
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - Lin Jia
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - Steven F Abcouwer
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
| | - David N Zacks
- Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
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Chen CL, Wu CY, Chen YL, Chen CC, Chang YT, Wu CY. Association between vitiligo and risk of retinal detachment: a population-based cohort study in Taiwan. Clin Exp Dermatol 2024; 49:841-847. [PMID: 38270273 DOI: 10.1093/ced/llae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/25/2023] [Accepted: 01/18/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND Vitiligo is reportedly associated with several ocular abnormalities. However, the relationship between vitiligo and retinal detachment (RD) remains unclear. OBJECTIVES To examine the risk of RD in patients with vitiligo. METHODS A nationwide population-based cohort study was conducted using data from the Taiwan National Health Insurance Database from 2007 to 2018. A total of 21 132 patients with vitiligo were matched in a 1 : 4 ratio with people without vitiligo by age, sex and comorbidity propensity score. Cumulative incidence and Cox proportional hazard models were used to investigate the risk of RD in patients with vitiligo. Subgroup analysis was performed. RESULTS The cohort with vitiligo had a significantly higher rate of RD than the cohort without vitiligo [adjusted hazard ratio (aHR) 1.44, 95% confidence interval (CI) 1.20-1.72; P < 0.001]. Patients with vitiligo who required treatments such as phototherapy, systemic corticosteroids or immunosuppressants exhibited an even greater risk of RD (aHR 1.57, 95% CI 1.16-2.14; P = 0.004). CONCLUSIONS Our study revealed a 1.44-fold increased risk of RD in patients with vitiligo, with an even higher risk in patients receiving phototherapy, systemic corticosteroids or immunosuppressants. The risk remained consistently higher over a 10-year follow-up period.
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Affiliation(s)
- Ching-Li Chen
- Department of Dermatology and Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Ying Wu
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Biomedical Informatics
- College of Public Health, China Medical University Taichung, Taiwan
| | | | - Chih-Chiang Chen
- Department of Dermatology and Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Dermatology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine and Institute of Public Health and Department of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yun-Ting Chang
- Department of Dermatology and Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Dermatology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chen-Yi Wu
- Department of Dermatology and Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Dermatology, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Public Health and Department of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
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Li S, Li M, Wu J, Li Y, Han J, Song Y, Cao W, Zhou X. Developing and validating a clinlabomics-based machine-learning model for early detection of retinal detachment in patients with high myopia. J Transl Med 2024; 22:405. [PMID: 38689321 PMCID: PMC11061938 DOI: 10.1186/s12967-024-05131-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 03/26/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Retinal detachment (RD) is a vision-threatening disorder of significant severity. Individuals with high myopia (HM) face a 2 to 6 times higher risk of developing RD compared to non-myopes. The timely identification of high myopia-related retinal detachment (HMRD) is crucial for effective treatment and prevention of additional vision impairment. Consequently, our objective was to streamline and validate a machine-learning model based on clinical laboratory omics (clinlabomics) for the early detection of RD in HM patients. METHODS We extracted clinlabomics data from the electronic health records for 24,440 HM and 5607 HMRD between 2015 and 2022. Lasso regression analysis assessed fifty-nine variables, excluding collinear variables (variance inflation factor > 10). Four models based on random forest, gradient boosting machine (GBM), generalized linear model, and Deep Learning Model were trained for HMRD diagnosis and employed for internal validation. An external test of the models was done. Three random data sets were further processed to validate the performance of the diagnostic model. The primary outcomes were the area under the receiver operating characteristic curve (AUC) and the area under the precision-recall curve (AUCPR) to diagnose HMRD. RESULTS Nine variables were selected by all models. Given the AUC and AUCPR values across the different sets, the GBM model was chosen as the final diagnostic model. The GBM model had an AUC of 0.8550 (95%CI = 0.8322-0.8967) and an AUCPR of 0.5584 (95%CI = 0.5250-0.5879) in the training set. The AUC and AUCPR in the internal validation were 0.8405 (95%CI = 0.8060-0.8966) and 0.5355 (95%CI = 0.4988-0.5732). During the external test evaluation, it reached an AUC of 0.7579 (95%CI = 0.7340-0.7840) and an AUCPR of 0.5587 (95%CI = 0.5345-0.5880). A similar discriminative capacity was observed in the three random data sets. The GBM model was well-calibrated across all the sets. The GBM-RD model was implemented into a web application that provides risk prediction for HM individuals. CONCLUSION GBM algorithms based on nine features successfully predicted the diagnosis of RD in patients with HM, which will help ophthalmologists to establish a preliminary diagnosis and to improve diagnostic accuracy in the clinic.
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Affiliation(s)
- Shengjie Li
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meiyan Li
- Department of Ophthalmology and Optometry, Fudan University Eye Ear Nose and Throat Hospital, Shanghai, China
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China
- Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China
- Shanghai Engineering Research Center of Laser and Autostereoscopic 3D for Vision Care, Shanghai, China
| | - Jianing Wu
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yingzhu Li
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianping Han
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yunxiao Song
- Department of Clinical Laboratory, Shanghai Xuhui Central Hospital, Fudan University, Shanghai, China.
| | - Wenjun Cao
- Department of Clinical Laboratory, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Xingtao Zhou
- Department of Ophthalmology and Optometry, Fudan University Eye Ear Nose and Throat Hospital, Shanghai, China.
- NHC Key Laboratory of Myopia (Fudan University), Shanghai, China.
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China.
- Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China.
- Shanghai Engineering Research Center of Laser and Autostereoscopic 3D for Vision Care, Shanghai, China.
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Abcouwer SF, Miglioranza Scavuzzi B, Kish PE, Kong D, Shanmugam S, Le XA, Yao J, Hager H, Zacks DN. The mouse retinal pigment epithelium mounts an innate immune defense response following retinal detachment. J Neuroinflammation 2024; 21:74. [PMID: 38528525 PMCID: PMC10964713 DOI: 10.1186/s12974-024-03062-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 03/11/2024] [Indexed: 03/27/2024] Open
Abstract
The retinal pigment epithelium (RPE) maintains photoreceptor viability and function, completes the visual cycle, and forms the outer blood-retinal barrier (oBRB). Loss of RPE function gives rise to several monogenic retinal dystrophies and contributes to age-related macular degeneration. Retinal detachment (RD) causes separation of the neurosensory retina from the underlying RPE, disrupting the functional and metabolic relationships between these layers. Although the retinal response to RD is highly studied, little is known about how the RPE responds to loss of this interaction. RNA sequencing (RNA-Seq) was used to compare normal and detached RPE in the C57BL6/J mouse. The naïve mouse RPE transcriptome was compared to previously published RPE signature gene lists and from the union of these 14 genes (Bmp4, Crim1, Degs1, Gja1, Itgav, Mfap3l, Pdpn, Ptgds, Rbp1, Rnf13, Rpe65, Slc4a2, Sulf1 and Ttr) representing a core signature gene set applicable across rodent and human RPE was derived. Gene ontology enrichment analysis (GOEA) of the mouse RPE transcriptome identified expected RPE features and functions, such as pigmentation, phagocytosis, lysosomal and proteasomal degradation of proteins, and barrier function. Differentially expressed genes (DEG) at 1 and 7 days post retinal detachment (dprd) were defined as mRNA with a significant (padj≤0.05) fold change (FC) of 0.67 ≥ FC ≥ 1.5 in detached versus naïve RPE. The RPE transcriptome exhibited dramatic changes at 1 dprd, with 2297 DEG identified. The KEGG pathways and biological process GO groups related to innate immune responses were significantly enriched. Lipocalin 2 (Lcn2) and several chemokines were upregulated, while numerous genes related to RPE functions, such as pigment synthesis, visual cycle, phagocytosis, and tight junctions were downregulated at 1 dprd. The response was largely transient, with only 18 significant DEG identified at 7 dprd, including upregulation of complement gene C4b. Validation studies confirmed RNA-Seq results. Thus, the RPE quickly downregulates cell-specific functions and mounts an innate immune defense response following RD. Our data demonstrate that the RPE contributes to the inflammatory response to RD and may play a role in attraction of immune cells to the subretinal space.
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Affiliation(s)
- Steven F Abcouwer
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA.
| | - Bruna Miglioranza Scavuzzi
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Phillip E Kish
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Dejuan Kong
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Sumathi Shanmugam
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Xuan An Le
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Jingyu Yao
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - Heather Hager
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
| | - David N Zacks
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medicine, 1000 Wall Street, Ann Arbor, MI, 48105, USA
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Maidana DE, Gonzalez-Buendia L, Pastor-Puente S, Naqvi A, Paschalis E, Kazlauskas A, Miller JW, Vavvas DG. Peripheral monocytes and neutrophils promote photoreceptor cell death in an experimental retinal detachment model. Cell Death Dis 2023; 14:834. [PMID: 38102109 PMCID: PMC10724298 DOI: 10.1038/s41419-023-06350-6] [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: 06/19/2023] [Revised: 10/31/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023]
Abstract
Photoreceptor cell death and immune cell infiltration are two major events that contribute to retinal degeneration. However, the relationship between these two events has not been well delineated, primarily because of an inadequate understanding of the immunological processes involved in photoreceptor degeneration, especially that of peripheral leukocytes that infiltrate the subretinal space and retinal tissues. In this work, we characterized the role of leukocyte infiltration within the detached retina. We observed that CD45+ CD11b+ Ly6G+ neutrophils and CD45+ CD11b+ Ly6G- Ly6C+ monocytes are the predominant peripheral immune cell populations that infiltrate the retinal and subretinal space after detachment. Selective depletion of monocytes or neutrophils using cell-specific targeting is neuroprotective for photoreceptors. These results indicate that peripheral innate immune cells contribute to photoreceptor degeneration, and targeting these immune cell populations could be therapeutic during retinal detachment.
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Affiliation(s)
- Daniel E Maidana
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Lucia Gonzalez-Buendia
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Sara Pastor-Puente
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
| | - Afsar Naqvi
- Mucosal Immunology Lab, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA
| | - Eleftherios Paschalis
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Andrius Kazlauskas
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, IL, USA
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, USA
| | - Joan W Miller
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Demetrios G Vavvas
- Retina Service, Angiogenesis Lab, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
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10
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Wang J, Lu L, Zou G, Ye Z, Jin F, Wang L, Ke G, Dong K, Tao L. Transcriptomic Analysis of Retinal Gene in Experimental Retinal Detachment Rats and Exploration of S100A9 and TLR4 in Human Vitreous. Curr Eye Res 2023; 48:1170-1178. [PMID: 37846082 DOI: 10.1080/02713683.2023.2254016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/28/2023] [Indexed: 10/18/2023]
Abstract
PURPOSE To screen for the differentially expressed genes in experimental retinal detachment rats, and to explore the expression of S100 calcium-binding protein A9 and Toll-like receptor 4 in the vitreous of rhegmatogenous retinal detachment patients. METHODS Three rats of experimental retinal detachment and three normal rats were enrolled in the study. Transcriptomics (RNAseq) sequencing technology was used to screen differentially expressed genes in the retinas of the experimental retinal detachment group and the normal group. The selected differentially expressed genes for gene ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis were performed. In addition, the vitreous of 15 patients with rhegmatogenous retinal detachment and six patients with the control group were collected. The expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were detected by Elisa, and the differences in expression levels were analyzed statistically. RESULTS A total of 198 differentially expressed genes were screened by RNAseq sequencing, including 118 upregulated genes and 80 downregulated genes. Kyoto Encyclopedia of Genes and Genomes analysis confirmed that the most enriched pathway was the mitogen-activated protein kinase signaling pathway. Compared to the normal group, the expressions of suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, and kinesin-light chain 1 mRNA in the retinas of the experimental retinal detachment rats were up-regulated, and the expressions of Max interacting protein 1 and the voltage-gated sodium 1 were down-regulated. Compared to the control group, the expressions of S100 calcium-binding protein A9 and Toll-like receptor 4 were upregulated by Elisa in the vitreous humor of rhegmatogenous retinal detachment patients with a statistically significant difference (p all <.05). CONCLUSION The differentially expressed genes of experimental retinal detachment rats were suppressor of cytokine signaling-3, Storkhead box-2, S100 calcium-binding protein A9, Spi-1 proto-oncogene, phosphodiesterase 1B, kinesin-light chain 1, Max interacting protein 1, voltage-gated sodium 1, etc. The differences of S100 calcium-binding protein A9 and Toll-like receptor 4 expressions between the rhegmatogenous retinal detachment patients and the control group were statistically significant, indicating that they may play a potential role in the inflammatory process of rhegmatogenous retinal detachment.
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Affiliation(s)
- Jing Wang
- Department of Ophthalmology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Li Lu
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Gaocheng Zou
- Department of Ophthalmology, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Ziyang Ye
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Feiyu Jin
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Lin Wang
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Genjie Ke
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Kai Dong
- Department of Ophthalmology, Division of Life Sciences and Medicine, Eye Center, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Liming Tao
- Department of Ophthalmology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
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11
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Wang Q, Wei WB, Shi XY, Rong WN. A novel PAX6 variant as the cause of aniridia in a Chinese patient with SRRRD. BMC Med Genomics 2023; 16:182. [PMID: 37542296 PMCID: PMC10401864 DOI: 10.1186/s12920-023-01620-w] [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: 01/27/2023] [Accepted: 07/30/2023] [Indexed: 08/06/2023] Open
Abstract
BACKGROUND The genotype characteristics and their associated clinical phenotypes in patients with aniridia were analyzed to explore pathogenic variants using whole-exome sequencing. METHODS One patient with aniridia was enrolled at the Beijing Tongren Hospital. Comprehensive ophthalmic and general examinations were performed on the patient. DNA was extracted from the patient, and whole-exome sequencing was performed to identify the causative variant. The pathogenicity of the variant was predicted using in silico analysis and evaluated according to American College of Medical Genetics and Genomics guidelines. Relationships between genetic variants and clinical features were analyzed. RESULTS In addition to the classical aniridia phenotype showing complete iris aplasia, foveal hypoplasia, and ectopic lentis, the patient also exhibited spontaneous reattachment rhegmatogenous retinal detachment (SRRRD). Whole-exome sequencing identified a novel heterozygous variant, exon8:c.640_646del:p.R214Pfs*28. CONCLUSIONS The present study broadens the range of genetic variants described in aniridia and presents an aniridia patient with SRRRD.
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Affiliation(s)
- Qian Wang
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, China. 1 Dong Jiao Min Xiang, Dong Cheng District, Beijing, 100730, China
| | - Wen Bin Wei
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, China. 1 Dong Jiao Min Xiang, Dong Cheng District, Beijing, 100730, China
| | - Xiang Yu Shi
- Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Medical Artificial Intelligence Research and Verification Laboratory of the Ministry of Industry and Information Technology, Beijing Tongren Hospital, Capital Medical University, China. 1 Dong Jiao Min Xiang, Dong Cheng District, Beijing, 100730, China.
| | - Wei Ning Rong
- Ningxia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, Third Clinical Medical College of Ningxia Medical University, Huanghe Road, Jinfeng District, the Ningxia Hui Autonomous Region, Yinchuan, 750002, China.
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12
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Xiao R, Lei C, Zhang Y, Zhang M. Interleukin-6 in retinal diseases: From pathogenesis to therapy. Exp Eye Res 2023:109556. [PMID: 37385535 DOI: 10.1016/j.exer.2023.109556] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/03/2023] [Accepted: 06/25/2023] [Indexed: 07/01/2023]
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that participates in immunomodulation, inflammation, increases vascular permeability, hematopoiesis, and stimulates cell proliferation, among other biological processes. It exerts effects primarily through the classic and trans-signaling pathways. Many studies have demonstrated that IL-6 plays a critical role in the development of retinal diseases including diabetic retinopathy, uveitis, age-related macular degeneration, glaucoma, retinal vein occlusion, central serous chorioretinopathy and proliferative vitreoretinopathy. Thus, the progressive development of drugs targeting IL-6 and IL-6 receptor may play a role in the treatment of multiple retinal diseases. In this article, we comprehensively review the IL-6's biological functions of and its mechanisms in the pathogenesis of various retinal diseases. Furthermore, we summarize the drugs targeting IL-6 and its receptor and prospect their potential application in retinal diseases, hoping to provide new ideas for the treatment of retinal diseases.
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Affiliation(s)
- Ruihan Xiao
- Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunyan Lei
- Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Zhang
- Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Meixia Zhang
- Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, 610041, China.
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13
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Zhou W, Zhou Y, He J, Rao Y, Fei P, Li J. TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment. Cell Death Dis 2023; 14:219. [PMID: 36977680 PMCID: PMC10050330 DOI: 10.1038/s41419-023-05735-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/03/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023]
Abstract
Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2-/-) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2-/- mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2-/- retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2-/- mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.
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Affiliation(s)
- Wenchuan Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yutong Zhou
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Jincan He
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Yuqing Rao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ping Fei
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Jing Li
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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14
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Prasad M, Xu J, Agranat JS, Xia W, Daley S, Ness S, Chen X, Siegel NH, Stein TD, Chung J, Subramanian ML. Upregulation of Neuroinflammatory Protein Biomarkers in Acute Rhegmatogenous Retinal Detachments. LIFE (BASEL, SWITZERLAND) 2022; 13:life13010118. [PMID: 36676067 PMCID: PMC9862737 DOI: 10.3390/life13010118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/20/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023]
Abstract
The purpose of this study is to characterize the inflammatory cytokine profile in rhegmatogenous retinal detachments (RRDs) compared to surgical controls. Vitreous humor was collected from patients undergoing vitrectomy for RRD and noninflammatory vitreoretinal diseases. A quantitative immunoassay was used to measure the levels of 36 cytokine markers. Linear regression analysis with the duration of detachment as the predictor and log-transformed cytokine levels as the outcome was conducted for normally distributed cytokines as determined by the Shapiro-Wilk test. The analysis was adjusted for age, sex, and race. The Kruskal-Wallis test was used for cytokines not normally distributed. Twenty-seven RRD cases and thirteen control cases were studied. Between all RRDs and controls, fibroblast growth factor 2 (FGF2) (p = 0.0029), inducible protein-10(IP-10) (p = 0.0021), monocyte chemoattractant protein-1 (MCP-1) (p = 0.0040), interleukin (IL)-16 (p = 0.018), IL-8 (p = 0.0148), IL-6 (p = 0.0071), eotaxin (p = 0.0323), macrophage inflammatory protein (MIP)-1 alpha (p = 0.0149), MIP-1 beta (p = 0.0032), and the thymus and activation regulated cytokine (TARC) (p = 0.0121) were elevated in RRD cases. Between acute RRDs (n = 16) and controls, FGF2 (p = 0.0001), IP10 (p = 0.0027), MCP-1 (p = 0.0015), MIP-1β (p = 0.0004), IL-8 (p = 0.0146), and IL-6 (p = 0.0031) were elevated. Determining alterations in inflammatory cytokine profiles may aid in understanding their impact on RRD development, clinical course, and complications before and after surgical repair.
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Affiliation(s)
- Minali Prasad
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Jia Xu
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Joshua S. Agranat
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Weiming Xia
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
- Geriatric Research Education and Clinical Center, VA Bedford Healthcare System, Bedford, MA 01730, USA
| | - Sarah Daley
- Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
- Geriatric Research Education and Clinical Center, VA Bedford Healthcare System, Bedford, MA 01730, USA
| | - Steven Ness
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Xuejing Chen
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Nicole H. Siegel
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
| | - Thor D. Stein
- Laboratory Medicine, Department of Pathology, Boston University School of Medicine, Boston, MA 02118, USA
- VA Bedford Healthcare System, Bedford, MA 01730, USA
- VA Boston Healthcare System, Boston, MA 02130, USA
| | - Jaeyoon Chung
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA
| | - Manju L. Subramanian
- Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA
- Correspondence: ; Tel.: +617-414-2020
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15
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Nortey A, Garces K, Carmy-Bennun T, Hackam AS. The cytokine IL-27 reduces inflammation and protects photoreceptors in a mouse model of retinal degeneration. J Neuroinflammation 2022; 19:216. [PMID: 36064575 PMCID: PMC9446869 DOI: 10.1186/s12974-022-02576-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Retinal degenerative diseases are a group of conditions characterized by photoreceptor death and vision loss. Excessive inflammation and microglial activation contribute to the pathology of retinal degenerations and a major focus in the field is identifying more effective anti-inflammatory therapeutic strategies that promote photoreceptor survival. A major challenge to developing anti-inflammatory treatments is to selectively suppress detrimental inflammation while maintaining beneficial inflammatory responses. We recently demonstrated that endogenous levels of the IL-27 cytokine were upregulated in association with an experimental treatment that increased photoreceptor survival. IL-27 is a pleiotropic cytokine that regulates tissue reactions to infection, neuronal disease and tumors by inducing anti-apoptotic and anti-inflammatory genes and suppressing pro-inflammatory genes. IL-27 is neuroprotective in the brain, but its function during retinal degeneration has not been investigated. In this study, we investigated the effect of IL-27 in the rd10 mouse model of inherited photoreceptor degeneration. METHODS Male and female rd10 mice were randomly divided into experimental (IL-27) and control (saline) groups and intravitreally injected at age post-natal day (P) 18. Retina function was analyzed by electroretinograms (ERGs), visual acuity by optomotor assay, photoreceptor death by TdT-mediated dUTP nick-end labeling (TUNEL) assay, microglia/macrophage were detected by immunodetection of IBA1 and inflammatory mediators by cytoplex and QPCR analysis. The distribution of IL-27 in the retina was determined by immunohistochemistry on retina cross-sections and primary Muller glia cultures. RESULTS We demonstrate that recombinant IL-27 decreased photoreceptor death, increased retinal function and reduced inflammation in the rd10 mouse model of retinal degeneration. Furthermore, IL-27 injections led to lower levels of the pro-inflammatory proteins Ccl22, IL-18 and IL-12. IL-27 expression was localized to Muller glia and IL-27 receptors to microglia, which are key cell types that regulate photoreceptor survival. CONCLUSION Our results identify for the first time anti-inflammatory and neuroprotective activities of IL-27 in a genetic model of retinal degeneration. These findings provide new insight into the therapeutic potential of anti-inflammatory cytokines as a treatment for degenerative diseases of the retina.
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Affiliation(s)
- Andrea Nortey
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Kimberly Garces
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Tal Carmy-Bennun
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Abigail S Hackam
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa. Int J Mol Sci 2021; 23:ijms23010070. [PMID: 35008496 PMCID: PMC8744961 DOI: 10.3390/ijms23010070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023] Open
Abstract
Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.
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17
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Postoperative proliferative vitreoretinopathy development is linked to vitreal CXCL5 concentrations. Sci Rep 2021; 11:23989. [PMID: 34907233 PMCID: PMC8671512 DOI: 10.1038/s41598-021-03294-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 11/30/2021] [Indexed: 11/11/2022] Open
Abstract
The specific changes linked to de novo development of postoperative PVR have remained elusive and were the object of the underlying study. Vitreous fluid (VF) was obtained at the beginning of vitrectomy from 65 eyes that underwent vitrectomy for primary rhegmatogenous retinal detachment (RRD) without preoperative PVR. Eyes developing postoperative PVR within 6 months after re-attachment surgery were compared to those which did not regarding the preoperative concentrations of 43 cytokines and chemokines in the VF, using multiplex beads analysis. For all comparisons Holm’s correction was applied in order to control for multiple comparisons. Twelve out of 65 eyes (18.5%) developed PVR postoperatively. While 12 of the chemokines and cytokines presented concentration differences on a statistical level of p < 0.05 (CXCL5, CCL11, CCL24, CCL26, GM-CSF, IFN-γ, CCL8, CCL7, MIF, MIG/CXCL9, CCL19, and CCL25), CXCL5 was the only cytokine with sufficiently robust difference in its VF concentrations to achieve significance in eyes developing postoperative PVR compared to eyes without PVR. CXCL5 may represent a potent biomarker for the de novo development of postoperative PVR. In line with its pathophysiological role in the development of PVR, it might serve as a basis for the development of urgently needed preventive options.
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18
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Conart JB, Augustin S, Remen T, Sahel JA, Guillonneau X, Delarasse C, Sennlaub F, Berrod JP. Vitreous cytokine expression profiles in patients with retinal detachment. J Fr Ophtalmol 2021; 44:1349-1357. [PMID: 34544594 DOI: 10.1016/j.jfo.2021.04.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/29/2021] [Accepted: 04/01/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE To compare the expression profiles of various cytokines and chemokines in vitreous samples from patients with retinal detachment (RD) to those from controls and to analyze their association with various clinical features. METHODS In this prospective study, undiluted vitreous fluid was obtained from 41 patients with primary RD and 33 controls with macular hole or vitreomacular traction. A multiplex bead immunoassay was performed to determine the expression of 27 inflammatory mediators. RESULTS Eleven mediators were significantly upregulated in the vitreous of RD patients compared with controls, including the following: cytokines IL-1ra, IL-6, IL-7, IL-8, IFN-γ; chemokines CCL2, CCL3, CCL4, CXCL10 and CCL11 and growth factor G-CSF. Correlation analyses showed that levels of IL-1ra, CXCL10, CCL11 and G-CSF were positively correlated to the extent of detachment, while those of IL-1ra and CXCL10 were associated with the duration of detachment. There was also a positive association between the concentrations of CXCL10 and CCL11 and preoperative flare values. Additional analysis revealed that flare values and both CXCL10 and CCL11 levels were significantly higher in eyes with grade B or C proliferative vitreoretinopathy (PVR). CONCLUSION Our results confirm that RD induces a marked inflammatory response with a complex cytokine network. We identified proteins specifically linked to several clinical features that might contribute to photoreceptor degeneration and PVR-related redetachment. These proteins may represent potential therapeutic targets for improving the anatomical and functional outcomes of RD surgery.
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Affiliation(s)
- J-B Conart
- Department of Ophthalmology, Nancy University Hospital, Vandœuvre-lès-Nancy, France; Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France.
| | - S Augustin
- Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France
| | - T Remen
- ESPRI-BioBase Unit, Platform of PARC, Nancy University Hospital, Vandœuvre-lès-Nancy, France
| | - J-A Sahel
- Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France
| | - X Guillonneau
- Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France
| | - C Delarasse
- Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France
| | - F Sennlaub
- Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, 17, rue Moreau, 75012 Paris, France
| | - J-P Berrod
- Department of Ophthalmology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
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19
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Orazbekov L, Zhanbolat K, Ruslanuly K. Cases of spontaneous reattachment of rhegmatogenous retinal detachment. Oxf Med Case Reports 2021; 2021:omab076. [PMID: 34527249 PMCID: PMC8436271 DOI: 10.1093/omcr/omab076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/06/2021] [Indexed: 11/18/2022] Open
Abstract
Report on clinical cases of spontaneous reattachment of rhegmatogenous retinal detachment (RRD). From 2014 to 2020 we diagnosed four patients with spontaneous reattachment of RRD. We conducted a review of the relevant medical records, focusing on the initial symptoms at presentation, the initial diagnoses, with a further observation of the patients next 3 years. The patients were re-examined 3 years later after cases of spontaneous reattachment of RRD. Three years after a case of spontaneous reattachment of RRD during reexamination in four patients (four eyes), redetachment was not detected. The mentioned clinical cases indicate the possibility of finding new approaches to RRD management.
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Affiliation(s)
- Lukpan Orazbekov
- First Ophthalmology Department, Kazakh Eye Research Institute, Almaty, Kazakhstan
| | - Kamilya Zhanbolat
- Postgraduate Education Department, Kazakh Eye Research Institute, Almaty, Kazakhstan
| | - Kairat Ruslanuly
- Postgraduate Education Department, Kazakh Eye Research Institute, Almaty, Kazakhstan
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20
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Abcouwer SF, Shanmugam S, Muthusamy A, Lin CM, Kong D, Hager H, Liu X, Antonetti DA. Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury. J Neuroinflammation 2021; 18:186. [PMID: 34446062 PMCID: PMC8394696 DOI: 10.1186/s12974-021-02237-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 02/08/2023] Open
Abstract
Background Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration. Methods Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. Results A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA. Conclusions These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02237-5.
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Affiliation(s)
- Steven F Abcouwer
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA.
| | - Sumathi Shanmugam
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | | | - Cheng-Mao Lin
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Dejuan Kong
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Heather Hager
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Xuwen Liu
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - David A Antonetti
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA.,Department of Molecular and Integrative Physiology, Ann Arbor, MI, 48109, USA
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21
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Differential Response of Müller Cells and Microglia in a Mouse Retinal Detachment Model and Its Implications in Detached and Non-Detached Regions. Cells 2021; 10:cells10081972. [PMID: 34440741 PMCID: PMC8394779 DOI: 10.3390/cells10081972] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 11/25/2022] Open
Abstract
Retinal detachment (RD) is a sight-threatening condition, leading to photoreceptor cell death; however, only a few studies provide insight into its effects on the entire retinal region. We examined the spatiotemporal changes in glial responses in a mouse RD model. In electroretinography, a- and b-waves were reduced in a time-dependent manner. Hematoxylin and eosin staining revealed a gradual decrease in the outer nuclear layer throughout the retinal region. Terminal deoxynucleotidyltransferase dUTP nick end labeling (TUNEL) assay showed that TUNEL-positive photoreceptors increased 5 days after RD and decreased by 14 days. Glial response was evaluated by immunohistochemistry using antibodies against glial fibrillary acidic protein (GFAP, Müller glial marker) and Iba-1 (microglial marker) and osteopontin (OPN, activated microglial marker). GFAP immunoreactivity increased after 7 days in complete RD, and was retained for 14 days. OPN expression increased in microglial cells 3–7 days after RD, and decreased by 14 days in the detached and border regions. Although OPN was not expressed in the intact region, morphologically activated microglial cells were observed. These retinal glial cell responses and photoreceptor degeneration in the border and intact regions suggest that the effects of RD in the border and intact retinal regions need to be understood further.
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22
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Balamurugan S, Das D, Hasanreisoglu M, Toy BC, Akhter M, Anuradha VK, Anthony E, Gurnani B, Kaur K. Interleukins and cytokine biomarkers in uveitis. Indian J Ophthalmol 2021; 68:1750-1763. [PMID: 32823391 PMCID: PMC7690463 DOI: 10.4103/ijo.ijo_564_20] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Interleukins and cytokines are involved in the pathogenesis of uveitis of heterogeneous origin. Understanding the basics of the ocular immune privilege is a fulcrum to discern their specific role in diverse uveitis to potentially translate as therapeutic targets. This review attempts to cover these elements in uveitis of infectious, noninfectious and masquerade origin. Insights of the molecular targets in novel therapy along with the vision of future research are intriguing.
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Affiliation(s)
- S Balamurugan
- Uveitis Services, Aravind Eye Hospital, Pondicherry, India
| | - Dipankar Das
- Department of Ocular Pathology, Uveitis and Neuro-Ophthalmology, Sri Sankaradeva Nethralaya, Guwahati, Assam, India
| | - Murat Hasanreisoglu
- Department of Ophthalmology, Koc University Medical School; Koc University Center for Translational Medicine Research, Istanbul; Department of Ophthalmology, Gazi University, School of Medicine, Ankara, Turkey
| | - Brian C Toy
- Assistant Professor of Clinical Ophthalmology, USC Roski Eye Institute, Los Angeles, USA
| | | | - V K Anuradha
- Uveitis Services, Aravind Eye Hospital, Coimbatore, Tamil Nadu, India
| | - Eliza Anthony
- Uveitis Services, Aravind Eye Hospital, Chennai, Tamil Nadu, India
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Zhang ZY, Sun YJ, Song JY, Fan B, Li GY. Experimental models and examination methods of retinal detachment. Brain Res Bull 2021; 169:51-62. [PMID: 33434623 DOI: 10.1016/j.brainresbull.2021.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 12/11/2020] [Accepted: 01/04/2021] [Indexed: 12/19/2022]
Abstract
Retinal detachment refers to the separation of the retinal neuroepithelium and pigment epithelium, usually involving the death of photoreceptor cells. Severe detachment may lead to permanent visual impairment if not treated properly and promptly. According to the underlying causes, retinal detachment falls into one of three categories: exudative retinal detachment, traction detachment, and rhegmatogenous retinal detachment. Like many other diseases, it is difficult to study the pathophysiology of retinal detachment directly in humans, because the human retinal tissues are precious, scarce and non-regenerative; thus, establishing experimental models that better mimic the disease is necessary. In this review, we summarize the existing models of the three categories of retinal detachment both in vivo and in vitro, along with an overview of their examination methods and the major strengths and weaknesses of each model.
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Affiliation(s)
- Zi-Yuan Zhang
- Second Hosp Jilin Univ, Dept Ophthalmol, 218 Zi Qiang St, Changchun, 130041, PR China.
| | - Ying-Jian Sun
- Second Hosp Jilin Univ, Dept Ophthalmol, 218 Zi Qiang St, Changchun, 130041, PR China.
| | - Jing-Yao Song
- Second Hosp Shandong Univ, Dept Ophthalmol, 247 Bei Yuan St, Jinan, 250031, PR China.
| | - Bin Fan
- Second Hosp Jilin Univ, Dept Ophthalmol, 218 Zi Qiang St, Changchun, 130041, PR China.
| | - Guang-Yu Li
- Second Hosp Jilin Univ, Dept Ophthalmol, 218 Zi Qiang St, Changchun, 130041, PR China.
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Lee SJ, Wang W, Jin L, Lu X, Gao L, Chen Y, Liu T, Emery D, Vukmanic E, Liu Y, Kaplan HJ, Dean DC. Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch. J Biol Chem 2021; 296:100102. [PMID: 33214223 PMCID: PMC7949052 DOI: 10.1074/jbc.ra120.016053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/13/2020] [Accepted: 11/19/2020] [Indexed: 01/19/2023] Open
Abstract
Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining their viability.
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Affiliation(s)
- Sang Joon Lee
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Ophthalmology, Kosin University College of Medicine, Seo-gu, Busan, Korea
| | - Wei Wang
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Lei Jin
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Xiaoqin Lu
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Lei Gao
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yao Chen
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
| | - Tingting Liu
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Ophthalmology, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
| | - Douglas Emery
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Eric Vukmanic
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Yongqing Liu
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Henry J Kaplan
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA
| | - Douglas C Dean
- Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
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25
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Gao W, Du J, Chi Y, Zhu R, Gao X, Yang L. Minocycline prevents the inflammatory response after retinal detachment, where microglia phenotypes being regulated through A20. Exp Eye Res 2020; 203:108403. [PMID: 33326811 DOI: 10.1016/j.exer.2020.108403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/08/2020] [Accepted: 12/10/2020] [Indexed: 12/14/2022]
Abstract
Retinal detachment (RD) is a severe sight-threatening complication that can be caused by a multitude of retinal diseases. It has been evidenced that minocycline exerts neuroprotective effects by targeting microglia in the pathogenesis of massive ocular lesions including RD, but mechanisms remain elusive. We carried out this research to elucidate the potential mediators that link RD-induced vision loss with microglia reactivity by discussing effects of minocycline on cytokine levels and A20, a negative regulator of inflammation. Minocycline or vehicle was intraperitoneally administrated immediately after RD and continued daily before animals being euthanized. The oxygen glucose deprivation assay was undertaken on the co-cultured BV-2 and 661W cells to mimic the condition of RD in vitro, where A20 siRNA was adopted to knock down the A20 expression in BV-2 cells. Photoreceptor cells apoptosis, inflammatory response and microglia activity following RD with or without minocycline were evaluated. Photoreceptor cells apoptosis and inflammatory response were induced after RD, which could be largely counteracted by minocycline. Minocycline postponed the migration and proliferation of microglia and facilitated their transition to the M2 subtype following RD. Blocking A20 expression in BV-2 cells with siRNA crippled the effect of minocycline. Collectively, minocycline yields a promoting effect on photoreceptor cells survival post-RD by modulating the transformation of microglia phenotypes, in which process A20 may play a "bridge" role.
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Affiliation(s)
- Wenna Gao
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China
| | - Jiantong Du
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China
| | - Ying Chi
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China
| | - Ruilin Zhu
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China
| | - Xinran Gao
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China
| | - Liu Yang
- Department of Ophthalmology, Peking University First Hospital, Beijing, PR China.
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26
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Conart JB, Blot G, Augustin S, Millet-Puel G, Roubeix C, Beguier F, Charles-Messance H, Touhami S, Sahel JA, Berrod JP, Léveillard T, Guillonneau X, Delarasse C, Sennlaub F. Insulin inhibits inflammation-induced cone death in retinal detachment. J Neuroinflammation 2020; 17:358. [PMID: 33243251 PMCID: PMC7694924 DOI: 10.1186/s12974-020-02039-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 11/17/2020] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Rhegmatogenous retinal detachment (RD) involving the macula is a major cause of visual impairment despite high surgical success rate, mainly because of cone death. RD causes the infiltration of activated immune cells, but it is not clear whether and how infiltrating inflammatory cells contribute to cone cell loss. METHODS Vitreous samples from patients with RD and from control patients with macular hole were analyzed to characterize the inflammatory response to RD. A mouse model of RD and retinal explants culture were then used to explore the mechanisms leading to cone death. RESULTS Analysis of vitreous samples confirms that RD induces a marked inflammatory response with increased cytokine and chemokine expression in humans, which is closely mimicked by experimental murine RD. In this model, we corroborate that myeloid cells and T-lymphocytes contribute to cone loss, as the inhibition of their accumulation by Thrombospondin 1 (TSP1) increased cone survival. Using monocyte/retinal co-cultures and TSP1 treatment in RD, we demonstrate that immune cell infiltration downregulates rod-derived cone viability factor (RdCVF), which physiologically regulates glucose uptake in cones. Insulin and the insulin sensitizers rosiglitazone and metformin prevent in part the RD-induced cone loss in vivo, despite the persistence of inflammation CONCLUSION: Our results describe a new mechanism by which inflammation induces cone death in RD, likely through cone starvation due to the downregulation of RdCVF that could be reversed by insulin. Therapeutic inhibition of inflammation and stimulation of glucose availability in cones by insulin signaling might prevent RD-associated cone death until the RD can be surgically repaired and improve visual outcome after RD. TRIAL REGISTRATION ClinicalTrials.gov NCT03318588.
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Affiliation(s)
- Jean-Baptiste Conart
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France.,Département d'Ophtalmologie, CHRU Nancy, Allée du Morvan, Vandoeuvre-lès-Nancy, France
| | - Guillaume Blot
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Sébastien Augustin
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Géraldine Millet-Puel
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Christophe Roubeix
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Fanny Beguier
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Hugo Charles-Messance
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Sara Touhami
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - José-Alain Sahel
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Jean-Paul Berrod
- Département d'Ophtalmologie, CHRU Nancy, Allée du Morvan, Vandoeuvre-lès-Nancy, France
| | - Thierry Léveillard
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France
| | - Xavier Guillonneau
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France.
| | - Cécile Delarasse
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France.
| | - Florian Sennlaub
- Institut de la Vision, INSERM, UMR_S 968, CNRS, Sorbonne Université, 17 rue Moreau, F-75012, Paris, France.
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The Immunomodulatory Potential of Mesenchymal Stem Cells in a Retinal Inflammatory Environment. Stem Cell Rev Rep 2020; 15:880-891. [PMID: 31863334 DOI: 10.1007/s12015-019-09908-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Retinal degenerative disorders are characterized by a local upregulation of inflammatory factors, infiltration with cells of the immune system, a vascular dysfunction and by the damage of retinal cells. There is still a lack of treatment protocols for these diseases. Mesenchymal stem cell (MSC)-based therapy using immunoregulatory, regenerative and differentiating properties of MSCs offers a promising treatment option. In this study, we analyzed the immunomodulatory properties of mouse bone marrow-derived MSCs after their intravitreal delivery to the inflammatory environment in the eye, caused by the application of pro-inflammatory cytokines IL-1β, TNF-α and IFN-γ. The intravitreal administration of these cytokines induces an increased expression of pro-inflammatory molecules such as IL-1α, IL-6, inducible nitric oxide synthase, TNF-α and vascular endothelial growth factor in the retina. However, a significant decrease in the expression of genes for all these pro-inflammatory molecules was observed after the intravitreal injection of MSCs. We further showed that an increased infiltration of the retina with immune cells, mainly with macrophages, which was observed after pro-inflammatory cytokine application, was significantly reduced after the intravitreal application of MSCs. The similar immunosuppressive effects of MSCs were also demonstrated in vitro in cultures of cytokine-stimulated retinal explants and MSCs. Overall, the results show that intravitreal application of MSCs inhibits the early retinal inflammation caused by pro-inflammatory cytokines, and propose MSCs as a promising candidate for stem cell-based therapy of retinal degenerative diseases.
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Chen X, Yang W, Deng X, Ye S, Xiao W. Interleukin-6 promotes proliferative vitreoretinopathy by inducing epithelial-mesenchymal transition via the JAK1/STAT3 signaling pathway. Mol Vis 2020; 26:517-529. [PMID: 32818015 PMCID: PMC7406861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 07/27/2020] [Indexed: 11/05/2022] Open
Abstract
Purpose Interleukin-6 (IL-6) is elevated in intraocular fluid from eyes with proliferative vitreoretinopathy (PVR), but the exact role of the cytokine is still unclear. We investigated the function and mechanism of IL-6 in retinal pigment epithelium (RPE) cell biology in vitro and in a mouse model in vivo. Methods After treatment with various concentrations of IL-6, RPE cell proliferation was assessed with cell counting kit-8 (CCK-8) assay, and epithelial-mesenchymal transition (EMT) markers were evaluated using western blotting and immunofluorescent staining. The activation of JAK1/STAT3 signaling was determined with western blotting. Moreover, the effects of blockade of IL-6/JAK1/STAT3 signaling were investigated using pharmacological inhibitor S3I-201. For in vivo studies, the PVR model was induced with intravitreal injection of dispase/collagenase in wild-type and IL-6 knockout mice. The severity of PVR was evaluated with histological analysis. The expression of IL-6, gp130, and EMT markers was assessed with quantitative real-time PCR and western blotting. Results IL-6 statistically significantly induced RPE cell proliferation and EMT in a dose-dependent manner in vitro, which was accompanied by rapid phosphorylation of JAK1 and STAT3. Blockade of the IL-6/JAK1/STAT3 pathway with S3I-201 apparently inhibited RPE proliferation and EMT. Furthermore, IL-6 and gp130 overexpression, and JAK1/STAT3 signaling hyperactivation were detected in the retinas of the wild-type mice at 1, 3, and 7 days after dispase/collagenase injection. Finally, we confirmed that IL-6 deficiency markedly alleviated mouse PVR development via inhibiting EMT. Conclusions These findings indicate that IL-6 promotes PVR by inducing RPE proliferation and EMT via the JAK1/STAT3 signaling pathway. We provided new evidence that therapeutic strategies to block IL-6 may be beneficial for PVR.
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Blockade of Adenosine A 2A Receptor Protects Photoreceptors after Retinal Detachment by Inhibiting Inflammation and Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7649080. [PMID: 32714489 PMCID: PMC7354651 DOI: 10.1155/2020/7649080] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 05/19/2020] [Accepted: 06/03/2020] [Indexed: 12/20/2022]
Abstract
Purpose Adenosine A2A receptor (A2AR) signaling is neuroprotective in some retinal damage models, but its role in neuronal survival during retinal detachment (RD) is unclear. We tested the hypothesis that A2AR antagonist ZM241385 would prevent photoreceptor apoptosis by inhibiting retinal inflammation and oxidative stress after RD. Methods The A2AR antagonist ZM241385 was delivered daily to C57BL/6J mice for three days at a dose (3 mg/kg, i.p.) starting 2 hours prior to creating RD. A2AR expression, microglia proliferation and reactivity, glial fibrillary acidic protein (GFAP) accumulation, IL-1β expression, and reactive oxygen species (ROS) production were evaluated with immunofluorescence. Photoreceptor TUNEL was analyzed. Results A2AR expression obviously increased and accumulated in microglia and Müller cells in the retinas after RD. The A2AR antagonist ZM241385 effectively inhibited retinal microglia proliferation and reactivity, decreased GFAP upregulation and proinflammatory cytokine IL-1β expression of Müller cells, and suppressed ROS overproduction, resulting in attenuation of photoreceptor apoptosis after RD. Conclusions The A2AR antagonist ZM241385 is an effective suppressor of microglia proliferation and reactivity, gliosis, neuroinflammation, oxidative stress, and photoreceptor apoptosis in a mouse model of RD. This suggests that A2AR blockade may be an important therapeutic strategy to protect photoreceptors in RD and other CNS diseases that share a common etiology.
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Li X, Liu Y, Sun M, Gao M, Li T, Liang J, Zhai Y, Xu M, She X, Yang S, Liu W, Luo X, Sun X. Photoreceptors Degenerate Through Pyroptosis After Experimental Retinal Detachment. Invest Ophthalmol Vis Sci 2020; 61:31. [PMID: 32697303 PMCID: PMC7425730 DOI: 10.1167/iovs.61.8.31] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Purpose Gasdermin D (GSDMD) is crucial in neuronal pyroptosis. GSDMD-N and GSDMD-C are two subdomains of the protein GSDMD. GSDMD-N is an executor of pyroptosis, and GSDMD-C has an inhibitory effect on pyroptotic cell death. This study evaluated the role of GSDMD in photoreceptor cell pyroptosis caused by retinal detachment (RD). Methods RD models were established in rats, and GSDMD cleavage was detected by western blotting. The morphology of photoreceptors was assessed by transmission electron microscopy. Some rats were given subretinal injections of recombinant adeno-associated virus 2/8 (rAAV2/8)–GSDMD-C before RD surgery. We documented the expression of caspase-1 and GSDMD-N in retinas by western blot. Levels of IL-1β, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) were detected by quantitative RT-PCR. The membrane integrity of photoreceptors was evaluated by TOTO-3 iodide staining. Retinal function was measured by electroretinography, and the thickness of the outer nuclear layer was also recorded. We measured the activation of glial fibrillary acidic protein (GFAP), F4/80, and ionized calcium binding adaptor molecule 1 (Iba-1) by immunofluorescence. Results The cleavage of GSDMD peaked at 1 day after RD. The administration of rAAV2/8–GSDMD-C reduced the pyroptosis and subsequent apoptosis of photoreceptors and preserved the retinal function after RD. Expression of IL-1, TNF-α, and MCP-1 was decreased in the rAAV2/8–GSDMD-C group. In addition, the activation of GFAP, Iba-1, and F4/80 in retinas was alleviated by administering rAAV2/8–GSDMD-C after RD. Conclusions GSDMD participates in the pyroptosis of photoreceptor after RD. Overexpression of GSDMD-C may block GSDMD cleavage and attenuate photoreceptor degeneration.
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Ross BX, Choi J, Yao J, Hager HM, Abcouwer SF, Zacks DN. Loss of High-Mobility Group Box 1 (HMGB1) Protein in Rods Accelerates Rod Photoreceptor Degeneration After Retinal Detachment. Invest Ophthalmol Vis Sci 2020; 61:50. [PMID: 32460314 PMCID: PMC7405795 DOI: 10.1167/iovs.61.5.50] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/13/2020] [Indexed: 02/07/2023] Open
Abstract
Purpose Retinal detachment (RD) disrupts the nutritional support and oxygen delivery to photoreceptors (PRs), ultimately causing cell death. High-mobility group box 1 (HMGB1) can serve as an extracellular alarmin when released from stressed cells. PRs release HMGB1 after RD. The purpose of this study was to investigate the relationship between HMGB1 and PR survival after RD. Methods Acute RD was created by injection of hyaluronic acid (1%) into the subretinal space in C57BL/6 mice and mice with a rhodopsin-Cre-mediated conditional knockout (cKO) of HMGB1 in rods (HMGB1ΔRod). Immunofluorescence (IF) in retinal sections was used to localize HMGB1, rhodopsin, and Iba-1 proteins. Optical coherence tomography and electroretinography were used to quantify retinal thickness and function, respectively. The morphology of the retina was assessed by hematoxylin and eosin. Results HMGB1 protein was localized to the nuclei of all retinal neurons, including PRs, with cones staining more intensely than rods. HMGB1 protein was also found in the inner and outer segments of cones but not rods. Creation of RD caused a dramatic increase of HMGB1 protein IF in rods. cKO of HMGB1 in rods did not affect retinal structure or function. However, after RD, loss of rods and reduction in the thickness of the outer nuclear layer were significantly increased in the HMGB1ΔRod retinas as compared to the control. Interestingly, depletion of HMGB1 in rods did not affect the activation and mobilization of microglia/macrophages normally seen after RD. Conclusions Increased HMGB1 expression in stressed rods may represent an intrinsic mechanism regulating their survival after RD.
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Affiliation(s)
- Bing X. Ross
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Joanne Choi
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Jingyu Yao
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Heather M. Hager
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Steven F. Abcouwer
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - David N. Zacks
- Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, Michigan, United States
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Yu S, Framme C, Menke MN, Berger LE, Zinkernagel MS, Munk MR, Wolf S, Ebneter A. Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study. Sci Rep 2020; 10:4948. [PMID: 32188915 PMCID: PMC7080767 DOI: 10.1038/s41598-020-61835-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 03/02/2020] [Indexed: 01/08/2023] Open
Abstract
We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Best-corrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients.
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Affiliation(s)
- Siqing Yu
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Carsten Framme
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Klinik für Augenheilkunde, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, Hannover, D-30625, Germany
| | - Marcel Nico Menke
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department of Ophthalmology, Kantonsspital Aarau, Herzogstrasse 15, Aarau, Switzerland
| | - Lieselotte Erika Berger
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Martin Sebastian Zinkernagel
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marion Rohit Munk
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Sebastian Wolf
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andreas Ebneter
- Department of Ophthalmology and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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Chaudhary R, Scott RAH, Wallace G, Berry M, Logan A, Blanch RJ. Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development. Transl Vis Sci Technol 2020; 9:23. [PMID: 32742753 PMCID: PMC7357815 DOI: 10.1167/tvst.9.3.23] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose Proliferative vitreoretinopathy (PVR) occurs in 5%-10% of rhegmatogenous retinal detachment cases and is the principle cause for failure of retinal reattachment surgery. Although there are a number of surgical adjunctive agents available for preventing the development of PVR, all have limited efficacy. Discovering predictive molecular biomarkers to determine the probability of PVR development after retinal reattachment surgery will allow better patient stratification for more targeted drug evaluations. Methods Narrative literature review. Results We provide a summary of the inflammatory and fibrogenic factors found in ocular fluid samples during the development of retinal detachment and PVR and discuss their possible use as molecular PVR predictive biomarkers. Conclusions Studies monitoring the levels of the above factors have found that few if any have predictive biomarker value, suggesting that widening the phenotype of potential factors and a combinatorial approach are required to determine predictive biomarkers for PVR. Translational Relevance The identification of relevant biomarkers relies on an understanding of disease signaling pathways derived from basic science research. We discuss the extent to which those molecules identified as biomarkers and predictors of PVR relate to disease pathogenesis and could function as useful disease predictors. (http://www.umin.ac.jp/ctr/ number, UMIN000005604).
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Affiliation(s)
- Rishika Chaudhary
- Academic Unit of Ophthalmology, Birmingham and Midland Eye Centre, Birmingham, UK.,Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.,NIHR Surgical Reconstruction and Microbiology Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Graham Wallace
- Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Martin Berry
- Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Ann Logan
- Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.,NIHR Surgical Reconstruction and Microbiology Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Richard J Blanch
- Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK.,NIHR Surgical Reconstruction and Microbiology Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Department of Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.,Academic Unit of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, UK
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Guo Y, Gao M, Wan X, Li X, Wang Y, Sun M, Li T, Jiang M, Luo X, Sun X. An improved method for establishment of murine retinal detachment model and its 3D vascular evaluation. Exp Eye Res 2020; 193:107949. [PMID: 32006561 DOI: 10.1016/j.exer.2020.107949] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/31/2019] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Retinal detachment (RD) results in disruption of retinal physiology and visual function. Although surgical intervention has been well-developed to restore the retinal anatomic structure, post-op progression of visual function decline is prominent in a large proportion of patients. Therefore, the establishment of a disease model that accurately mimics RD pathogenesis is crucial to mechanistic study and drug screening. General protocols to induce RD in mice are frequently associated with complications leading to model instability and reduced reproducibility. In this study, we established a stable and reproducible mice RD model with a detached area of over 90% and rare complications. Briefly, the modified method was realized by vitreous humor extraction to reduce intraocular pressure, followed by directly-visible hyaluronic acid injection into subretinal space. The detachment of retina was confirmed by fundus photography, and progressive thinning of the outer nuclear layer (ONL) was determined by HE staining. Apoptotic signals were prominent in the ONL. Consistently, visual function was significantly compromised as determined by ERG. Moreover, retinal vasculature appeared to remodel and acquired winding, twisted and dilated structures illustrated by 3D reconstruction. In addition, activation of Müller cells and microglia, and infiltration of blood-derived macrophages were detected locally. Collectively, we have established a modified protocol to model RD with increased stability, reproducibility and fewer complications, and 3D high-resolution imaging and reconstruction of vasculature could provide new tools to evaluate this model.
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Affiliation(s)
- Yinong Guo
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Min Gao
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Xiaoling Wan
- Shanghai Key Laboratory of Fundus Diseases, 200080, Shanghai, China
| | - Xiaomeng Li
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Yimin Wang
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Mengsha Sun
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Tong Li
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China
| | - Mei Jiang
- Shanghai Key Laboratory of Fundus Diseases, 200080, Shanghai, China
| | - Xueting Luo
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China; Shanghai Key Laboratory of Fundus Diseases, 200080, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, 200080, Shanghai, China.
| | - Xiaodong Sun
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University, School of Medicine, 200080, Shanghai, China; Shanghai Key Laboratory of Fundus Diseases, 200080, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, 200080, Shanghai, China; National Clinical Research Center for Eye Diseases, 200080, Shanghai, China; Shanghai engineering center for precise diagnosis and treatment of eye diseases, 200080, Shanghai, China.
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35
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Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells - a clue to stem cell-based therapy. World J Stem Cells 2019; 11:957-967. [PMID: 31768222 PMCID: PMC6851013 DOI: 10.4252/wjsc.v11.i11.957] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/02/2019] [Accepted: 09/14/2019] [Indexed: 02/06/2023] Open
Abstract
Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.
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Affiliation(s)
- Vladimir Holan
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Barbora Hermankova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Magdalena Krulova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague 12843, Czech Republic
| | - Alena Zajicova
- Department of Transplantation Immunology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 14220, Czech Republic
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36
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Oxidative Stress, Lipid Peroxidation, and Loss of Hyaluronic Acid in the Human Vitreous Affected by Synchysis Scintillans. J Ophthalmol 2019; 2019:7231015. [PMID: 31781380 PMCID: PMC6875268 DOI: 10.1155/2019/7231015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 09/06/2019] [Indexed: 01/22/2023] Open
Abstract
The aim of this study was to assess the oxidative stress status in eyes affected by synchysis scintillans and to compare it to vitreoretinal disorders without synchysis scintillans. Human aqueous and vitreous humors were obtained during vitrectomy from thirty-seven otherwise healthy patients that were randomly chosen among patients that had to undergo a 25-gauge pars plana vitrectomy from the central vitreous cavity, for either synchysis scintillans (n = 16) or vitreoretinal disorders without synchysis scintillans (n = 21), such as idiopathic epimacular membrane (n = 12), macular hole (n = 5), or rhegmatogenous retinal detachment (n = 4). The redox parameters thiobarbituric acid reactive substances (TBARS), a measurement of lipid peroxidation, nitrite concentration, an estimate of nitric oxide (NO) production, 4-hydroxynonenal (4-HNE)-protein conjugates, a structural protein modification by lipid peroxidation product 4-HNE, and the antioxidative activities of Cu,Zn-superoxide dismutase (SOD), and catalase were measured in aqueous and vitreous humors and compared between synchysis scintillans affected and not-affected patients. TBARS and nitrite levels of the vitreous humor were significantly higher in patients with synchysis scintillans as compared to patients affected by vitreoretinal disorders without synchysis scintillans. Synchysis scintillans patients had significantly lower activities of SOD and catalase both in aqueous and vitreous humors than patients with vitreoretinal disorders without synchysis. The consequently higher lipoperoxide-dependent 4-HNE production in synchysis scintillans was detectable in aqueous and vitreous humors as a significant increased accumulation of 4-HNE-protein conjugates vs nonsynchysis vitreoretinal disorders. Additionally, hyaluronic acid (HA) was significantly decreased in the vitreous body of synchysis scintillans patients. The data consistently show that synchisis scintillans is accompanied by a redox imbalance with increased oxidative modifications of 4-HNE proteins and loss of HA, both of likely importance for remote damages of the retina. It remains to be proven whether a therapeutic strategy which targets oxidative stress may be effective in the treatment of synchysis patients.
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Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases. Front Immunol 2019; 10:1618. [PMID: 31379825 PMCID: PMC6646526 DOI: 10.3389/fimmu.2019.01618] [Citation(s) in RCA: 160] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/28/2019] [Indexed: 12/22/2022] Open
Abstract
Inflammation underpins and contributes to the pathogenesis of many retinal degenerative diseases. The recruitment and activation of both resident microglia and recruited macrophages, as well as the production of cytokines, are key contributing factors for progressive cell death in these diseases. In particular, the interleukin 1 (IL-1) family consisting of both pro- and anti-inflammatory cytokines has been shown to be pivotal in the mediation of innate immunity and contribute directly to a number of retinal degenerations, including Age-Related Macular Degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, glaucoma, and retinopathy of prematurity (ROP). In this review, we will discuss the role of IL-1 family members and inflammasome signaling in retinal degenerative diseases, piecing together their contribution to retinal disease pathology, and identifying areas of research expansion required to further elucidate their function in the retina.
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Affiliation(s)
- Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Si Ming Man
- 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
| | - 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
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38
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Zandi S, Pfister IB, Traine PG, Tappeiner C, Despont A, Rieben R, Skowronska M, Garweg JG. Biomarkers for PVR in rhegmatogenous retinal detachment. PLoS One 2019; 14:e0214674. [PMID: 30943234 PMCID: PMC6447182 DOI: 10.1371/journal.pone.0214674] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 03/18/2019] [Indexed: 12/28/2022] Open
Abstract
PURPOSE Various profibrotic and proinflammatory cytokines have been found upregulated in uncomplicated primary retinal detachment (pRD), but without providing a uniform picture. Here, we compare the cyto- and chemokine profiles in pRD with and without proliferative vitreoretinopathy (PVR) in an attempt to unravel relevant differences not in single cytokines, but in the cytokine profiles at diagnosis. METHODS Undiluted vitreous fluid (VF) was obtained at the beginning of surgery from 174 eyes with pRD without relevant PVR (maximally grade B; group 1; n = 81) and with moderate or advanced PVR requiring a gas tamponade (group 2; n = 49) or silicon oil filling (group 3; n = 44). VF of eyes undergoing macular hole (MH) surgery served as controls (group 4; n = 26). Forty-three cytokines were quantified in parallel using a multiplex cytokine analysis system (Bioplex). For all comparisons we applied Holm's correction to control for multiple comparisons. RESULTS 44.9% of group 2 eyes presented grade C1 and 55.1% C2-C3, whereas 86.4% of group 3 eyes exhibited a PVR grade of C2-D. CCL19 was the only cytokine that displayed higher concentrations in the vitreous of eyes with PVR C1 compared to lower PVR grades. Eyes with PVR C2-D showed higher levels of CCL27, CXCL6, IL4, IL16, CXCL10, CCL8, CCL22, MIG/CXCL9, CCL15, CCL19, CCL 23 and CXCL12 compared to controls. Interestingly, no difference of cytokine levels was detected between C1 and C2-D PVR. CONCLUSIONS CCL19 may represent a potential biomarker for early PVR progression that holds promise for future diagnostic and therapeutic applications.
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Affiliation(s)
- Souska Zandi
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik am Lindenhof-Spital, Bern, Switzerland
| | - Isabel B. Pfister
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik am Lindenhof-Spital, Bern, Switzerland
| | - Peter G. Traine
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik am Lindenhof-Spital, Bern, Switzerland
| | - Christoph Tappeiner
- Department of Ophthalmology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Alain Despont
- Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Robert Rieben
- Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Magdalena Skowronska
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik am Lindenhof-Spital, Bern, Switzerland
| | - Justus G. Garweg
- Swiss Eye Institute and Clinic for Vitreoretinal Diseases, Berner Augenklinik am Lindenhof-Spital, Bern, Switzerland
- University of Bern, Bern, Switzerland
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