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Ahmadi S, Gohari-Lasaki S, Jahangiri N, Ejlalidiz M, Saberiyan M. The multifaceted roles of exosomes in corneal biology: elucidation of underlying mechanisms and therapeutic applications. Mol Biol Rep 2025; 52:527. [PMID: 40448864 DOI: 10.1007/s11033-025-10642-9] [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: 02/22/2025] [Accepted: 05/22/2025] [Indexed: 06/02/2025]
Abstract
The cornea, as the essential part of the eye with the duty of maintaining transparency and vision, is susceptible to various diseases and genetic abnormalities. Vision loss due to corneal disorders is a global concern, prompting research into innovative treatment approaches. The investigations have provided a significant role that exosomes play in maintaining corneal homeostasis and promoting intercellular communication. The cornea is made up of cellular and acellular components. The cellular components include the epithelial cells, stromal keratocytes, and endothelial cells, which secrete exosomes that contribute to preserving corneal transparency, immune privilege, and tissue repair. These nanosized vesicles contain molecules that regulate immune responses, promote cell proliferation and migration, and protect against stress-induced cell death. In this review, we try to survey the therapeutic potential and effects of exosomes in treating various corneal conditions, which can contribute to enhance corneal healing, reduce scarring, and improve visual outcomes.
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Affiliation(s)
- Samaneh Ahmadi
- Department of Medical Genetics, Faculty of Medicine, School of Medical Sciences, Hormozgan University of Medical Sciences, P.O.Box: 7919693116, Bandar Abbas, Iran
| | - Sahar Gohari-Lasaki
- Endocrine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Jahangiri
- Department of Biology, Faculty of Basic Sciences and Engineering, Gonbad Kavous University, Gonbad Kavous, Iran
| | - Mahsa Ejlalidiz
- Medical Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammadreza Saberiyan
- Department of Medical Genetics, Faculty of Medicine, School of Medical Sciences, Hormozgan University of Medical Sciences, P.O.Box: 7919693116, Bandar Abbas, Iran.
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
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2
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Oladapo A, Kannan M, Deshetty UM, Singh S, Buch S, Periyasamy P. Methamphetamine-mediated astrocytic pyroptosis and neuroinflammation involves miR-152-NLRP6 inflammasome signaling axis. Redox Biol 2025; 80:103517. [PMID: 39879739 PMCID: PMC11810843 DOI: 10.1016/j.redox.2025.103517] [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: 12/24/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 01/31/2025] Open
Abstract
Methamphetamine is a widely abused drug associated with significant neuroinflammation and neurodegeneration, mainly through the activation of glial cells and neurons in the central nervous system. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that methamphetamine exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces methamphetamine-induced pyroptosis and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in methamphetamine-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating methamphetamine-induced pyroptosis and inflammation. In vivo and ex vivo studies in methamphetamine-exposed mice confirmed these results and showed that methamphetamine induces anxiety-like, cognitive impairment, and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to methamphetamine-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate methamphetamine-induced central nervous system pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for methamphetamine-related neurological disorders.
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Affiliation(s)
- Abiola Oladapo
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Muthukumar Kannan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Uma Maheswari Deshetty
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Seema Singh
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Shilpa Buch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA
| | - Palsamy Periyasamy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
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Torkashvand A, Hajrasouliha A. Exosome's Implications in Age-Related Macular Degeneration. Curr Eye Res 2025:1-8. [PMID: 39854159 DOI: 10.1080/02713683.2025.2457105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/02/2024] [Accepted: 01/16/2025] [Indexed: 01/26/2025]
Abstract
PURPOSE This study aims to conduct a mini review of published literature concerning the role of exosomes in the field of ophthalmology, with a specific focus on Age-Related Macular Degeneration (AMD). METHODS In this study, a comprehensive search was conducted using PubMed and Google Scholar to identify relevant publications. Additionally, trials submitted to clinicaltrials.gov were reviewed to identify further relevant articles. The selected studies specifically focused on the ocular implications of exosomes in Age-Related Macular Degeneration. RESULTS Exosomes, small extracellular vesicles measuring less than 200 nm, play a crucial role in cell signaling and are involved in various physiological and pathological processes. Recent research has focused on utilizing exosomes for disease detection and treatment. Studies have investigated the ocular implications of exosomes, particularly in AMD. Exosomes found in aqueous fluid and blood have been examined as potential markers for AMD and as indicators of treatment response. Additionally, research in animal models has indicated the potential of exosomes in preventing AMD, as well as their promise for targeted and efficient drug delivery. This mini review primarily emphasizes the clinical aspects of publications related to AMD, rather than focusing solely on basic science. CONCLUSIONS Exosomes have a great potential for understanding Age-related Macular Degeneration and effective and targeted treatment for retinal diseases.
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Affiliation(s)
- Ali Torkashvand
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Amir Hajrasouliha
- Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA
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Wu D, Zhao X, Xie J, Yuan R, Li Y, Yang Q, Cheng X, Wu C, Wu J, Zhu N. Physical modulation of mesenchymal stem cell exosomes: A new perspective for regenerative medicine. Cell Prolif 2024; 57:e13630. [PMID: 38462759 PMCID: PMC11294442 DOI: 10.1111/cpr.13630] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/29/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exo) offer promising therapeutic potential for various refractory diseases, presenting a novel therapeutic strategy. However, their clinical application encounters several obstacles, including low natural secretion, uncontrolled biological functions and inherent heterogeneity. On the one hand, physical stimuli can mimic the microenvironment dynamics where MSC-Exo reside. These factors influence not only their secretion but also, significantly, their biological efficacy. Moreover, physical factors can also serve as techniques for engineering exosomes. Therefore, the realm of physical factors assumes a crucial role in modifying MSC-Exo, ultimately facilitating their clinical translation. This review focuses on the research progress in applying physical factors to MSC-Exo, encompassing ultrasound, electrical stimulation, light irradiation, intrinsic physical properties, ionizing radiation, magnetic field, mechanical forces and temperature. We also discuss the current status and potential of physical stimuli-affected MSC-Exo in clinical applications. Furthermore, we address the limitations of recent studies in this field. Based on this, this review provides novel insights to advance the refinement of MSC-Exo as a therapeutic approach in regenerative medicine.
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Affiliation(s)
- Dan Wu
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Xiansheng Zhao
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Jiaheng Xie
- Department of Plastic SurgeryXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Ruoyue Yuan
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Yue Li
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Quyang Yang
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Xiujun Cheng
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Changyue Wu
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
| | - Jinyan Wu
- Department of DermatologyChongzhou People's HospitalChengduChina
| | - Ningwen Zhu
- Department of DermatologyHuashan Hospital, Fudan UniversityShanghaiChina
- Department of PlasticReconstructive and Burns Surgery, Huashan Hospital, Fudan UniversityShanghaiChina
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Zhang Z, Gu Q, Chen L, Yuan D, Gu X, Qian H, Xie P, Liu Q, Hu Z. Selective microRNA expression of exosomes from retinal pigment epithelial cells by oxidative stress. Vision Res 2024; 220:108388. [PMID: 38593635 DOI: 10.1016/j.visres.2024.108388] [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: 09/10/2023] [Revised: 03/15/2024] [Accepted: 03/16/2024] [Indexed: 04/11/2024]
Abstract
The function of exosomal miRNAs (miRs) in retinal degeneration is largely unclear. We were aimed to investigate the functions of exosomes as well as their miRs derived from retinal pigment epithelial (RPE) cells following exposure to oxidative stress (OS). After the OS by lipopolysaccharide and rotenone on RPE cells, interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) were upregulated, along with the decreased mitochondrial membrane potential and upregulated oxidative damage marker 8-OH-dG in RPE cells. RPE-derived exosomes were then isolated, identified, injected into the subretinal space in mice. After subretinal injection, RPE-exosomes after OS not only induced higher ROS level and apoptotic retinal cells, but also elevated IL-1β, IL-6 alongside TNF-α expressions among retina/RPE/choroidal complex. Next, miRs inside the exosomes were sequenced by the next generation sequencing (NGS) technology. NGS revealed that certain miRs were abundant in exosomes, while others were selectively kept by RPE cells. Further, downregulated miRs, like miR-125b-5p, miR-125a-5p, alongside miR-128-3p, and upregulated miR, such as miR-7-5p were validated byRT-qPCR. Finally, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to find the possible target genes of those selective exosomal miRs. Our results proved that the RPE-derived exosomes after OS selectively express certain miRs, providing novel insights into the pathogenesis of age-related macular degeneration (AMD) in future.
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Affiliation(s)
- Zhengyu Zhang
- Department of Ophthalmology, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University. Xuzhou, Jiangsu 221116, China
| | - Qinyuan Gu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Lu Chen
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China; Department of Ophthalmology, Xuzhou First People's Hospital, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University. Xuzhou, Jiangsu 221116, China
| | - Dongqing Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Xunyi Gu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Huiming Qian
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China; Department of Ophthalmology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Ping Xie
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China.
| | - Zizhong Hu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University. Nanjing, Jiangsu 210029, China.
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Yang SN, Shi Y, Berggren PO. The anterior chamber of the eye technology and its anatomical, optical, and immunological bases. Physiol Rev 2024; 104:881-929. [PMID: 38206586 PMCID: PMC11381035 DOI: 10.1152/physrev.00024.2023] [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: 06/20/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology.
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Affiliation(s)
- Shao-Nian Yang
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yue Shi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
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Martins B, Pires M, Ambrósio AF, Girão H, Fernandes R. Contribution of extracellular vesicles for the pathogenesis of retinal diseases: shedding light on blood-retinal barrier dysfunction. J Biomed Sci 2024; 31:48. [PMID: 38730462 PMCID: PMC11088087 DOI: 10.1186/s12929-024-01036-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 04/30/2024] [Indexed: 05/12/2024] Open
Abstract
Retinal degenerative diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), loom as threats to vision, causing detrimental effects on the structure and function of the retina. Central to understanding these diseases, is the compromised state of the blood-retinal barrier (BRB), an effective barrier that regulates the influx of immune and inflammatory components. Whether BRB breakdown initiates retinal distress, or is a consequence of disease progression, remains enigmatic. Nevertheless, it is an indication of retinal dysfunction and potential vision loss.The intricate intercellular dialogues among retinal cell populations remain unintelligible in the complex retinal milieu, under conditions of inflammation and oxidative stress. The retina, a specialized neural tissue, sustains a ceaseless demand for oxygen and nutrients from two vascular networks. The BRB orchestrates the exchange of molecules and fluids within this specialized region, comprising the inner BRB (iBRB) and the outer BRB (oBRB). Extracellular vesicles (EVs) are small membranous structures, and act as messengers facilitating intercellular communication in this milieu.EVs, both from retinal and peripheral immune cells, increase complexity to BRB dysfunction in DR and AMD. Laden with bioactive cargoes, these EVs can modulate the retinal microenvironment, influencing disease progression. Our review delves into the multifaceted role of EVs in retinal degenerative diseases, elucidating the molecular crosstalk they orchestrate, and their microRNA (miRNA) content. By shedding light on these nanoscale messengers, from their biogenesis, release, to interaction and uptake by target cells, we aim to deepen the comprehension of BRB dysfunction and explore their therapeutic potential, therefore increasing our understanding of DR and AMD pathophysiology.
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Affiliation(s)
- Beatriz Martins
- University Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, 3000- 548, Portugal
- University of Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra, 3000-548, Portugal
- University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, 3004-531, Portugal
| | - Maria Pires
- University Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, 3000- 548, Portugal
- University of Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra, 3000-548, Portugal
- University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, 3004-531, Portugal
| | - António Francisco Ambrósio
- University Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, 3000- 548, Portugal
- University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, 3004-531, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, 3004-561, Portugal
- Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, 3000-548, Portugal
| | - Henrique Girão
- University Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, 3000- 548, Portugal
- University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, 3004-531, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, 3004-561, Portugal
| | - Rosa Fernandes
- University Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, 3000- 548, Portugal.
- University of Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra, 3000-548, Portugal.
- University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, 3004-531, Portugal.
- Clinical Academic Center of Coimbra (CACC), Coimbra, 3004-561, Portugal.
- Association for Innovation and Biomedical Research on Light and Image (AIBILI), Coimbra, 3000-548, Portugal.
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8
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Brandli A, Vessey KA, Fletcher EL. The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome. J Neuroinflammation 2024; 21:64. [PMID: 38443987 PMCID: PMC10913318 DOI: 10.1186/s12974-024-03055-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/26/2024] [Indexed: 03/07/2024] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, characterised by the dysfunction and death of the photoreceptors and retinal pigment epithelium (RPE). Innate immune cell activation and accompanying para-inflammation have been suggested to contribute to the pathogenesis of AMD, although the exact mechanism(s) and signalling pathways remain elusive. Pattern recognition receptors (PRRs) are essential activators of the innate immune system and drivers of para-inflammation. Of these PRRs, the two most prominent are (1) Toll-like receptors (TLR) and (2) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-inflammasome have been found to modulate the progression of AMD. Mutations in TLR2 have been found to be associated with an increased risk of developing AMD. In animal models of AMD, inhibition of TLR and NLRP3 has been shown to reduce RPE cell death, inflammation and angiogenesis signalling, offering potential novel treatments for advanced AMD. Here, we examine the evidence for PRRs, TLRs2/3/4, and NLRP3-inflammasome pathways in macular degeneration pathogenesis.
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Affiliation(s)
- Alice Brandli
- Department of Anatomy and Physiology, The University of Melbourne, Grattan St, Parkville, Victoria, 3010, Australia
- Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Kirstan A Vessey
- Department of Anatomy and Physiology, The University of Melbourne, Grattan St, Parkville, Victoria, 3010, Australia
| | - Erica L Fletcher
- Department of Anatomy and Physiology, The University of Melbourne, Grattan St, Parkville, Victoria, 3010, Australia.
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Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
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Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
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Korhonen E. Inflammasome activation in response to aberrations of cellular homeostasis in epithelial cells from human cornea and retina. Acta Ophthalmol 2024; 102 Suppl 281:3-68. [PMID: 38386419 DOI: 10.1111/aos.16646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 01/16/2024] [Indexed: 02/24/2024]
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Romero FJ, Diaz-Llopis M, Romero-Gomez MI, Miranda M, Romero-Wenz R, Sancho-Pelluz J, Romero B, Muriach M, Barcia JM. Small Extracellular Vesicles and Oxidative Pathophysiological Mechanisms in Retinal Degenerative Diseases. Int J Mol Sci 2024; 25:1618. [PMID: 38338894 PMCID: PMC10855665 DOI: 10.3390/ijms25031618] [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: 01/03/2024] [Revised: 01/20/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles' cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.
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Affiliation(s)
- Francisco J. Romero
- Hospital General de Requena, Conselleria de Sanitat, Generalitat Valenciana, 46340 Requena, Spain;
| | - Manuel Diaz-Llopis
- Facultad de Medicina y Odontología, Universitat de València, 46010 Valencia, Spain;
| | | | - Maria Miranda
- Facultad de Ciencias de la Salud, Universidad CEU-Cardenal Herrera, 46115 Alfara del Patriarca, Spain;
| | - Rebeca Romero-Wenz
- Hospital General de Requena, Conselleria de Sanitat, Generalitat Valenciana, 46340 Requena, Spain;
| | - Javier Sancho-Pelluz
- Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia, 46001 Valencia, Spain; (J.S.-P.); (B.R.); (J.M.B.)
| | - Belén Romero
- Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia, 46001 Valencia, Spain; (J.S.-P.); (B.R.); (J.M.B.)
- Unidad de Cuidados intensivos, Hospital de Manises, 46940 Manises, Spain
| | - Maria Muriach
- Facultad de Ciencias de la Salud, Universitat Jaume I, 12006 Castelló de la Plana, Spain;
| | - Jorge M. Barcia
- Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia, 46001 Valencia, Spain; (J.S.-P.); (B.R.); (J.M.B.)
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12
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Manai F, Smedowski A, Kaarniranta K, Comincini S, Amadio M. Extracellular vesicles in degenerative retinal diseases: A new therapeutic paradigm. J Control Release 2024; 365:448-468. [PMID: 38013069 DOI: 10.1016/j.jconrel.2023.11.035] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/03/2023] [Accepted: 11/18/2023] [Indexed: 11/29/2023]
Abstract
Nanoscale extracellular vesicles (EVs), consisting of exomers, exosomes and microvesicles/ectosomes, have been extensively investigated in the last 20 years, although their biological role is still something of a mystery. EVs are involved in the transfer of lipids, nucleic acids and proteins from donor to recipient cells or distant organs as well as regulating cell-cell communication and signaling. Thus, EVs are important in intercellular communication and this is not limited to sister cells, but may also mediate the crosstalk between different cell types even over long distances. EVs play crucial functions in both cellular homeostasis and the pathogenesis of diseases, and since their contents reflect the status of the donor cell, they represent an additional valuable source of information for characterizing complex biological processes. Recent advances in isolation and analytical methods have led to substantial improvements in both characterizing and engineering EVs, leading to their use either as novel biomarkers for disease diagnosis/prognosis or even as novel therapies. Due to their capacity to carry biomolecules, various EV-based therapeutic applications have been devised for several pathological conditions, including eye diseases. In the eye, EVs have been detected in the retina, aqueous humor, vitreous body and also in tears. Experiences with other forms of intraocular drug applications have opened new ways to use EVs in the treatment of retinal diseases. We here provide a comprehensive summary of the main in vitro, in vivo, and ex vivo literature-based studies on EVs' role in ocular physiological and pathological conditions. We have focused on age-related macular degeneration, diabetic retinopathy, glaucoma, which are common eye diseases leading to permanent blindness, if not treated properly. In addition, the putative use of EVs in retinitis pigmentosa and other retinopathies is discussed. Finally, we have reviewed the potential of EVs as therapeutic tools and/or biomarkers in the above-mentioned retinal disorders. Evidence emerging from experimental disease models and human material strongly suggests future diagnostic and/or therapeutic exploitation of these biological agents in various ocular disorders with a good possibility to improve the patient's quality of life.
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Affiliation(s)
- Federico Manai
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
| | - Adrian Smedowski
- Department of Ophthalmology, Faculty of Medical Sciences in Katowice, Medical University of Silesia in Katowice, Katowice, Poland; GlaucoTech Co., Katowice, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland; Department of Molecular Genetics, University of Lodz, Lodz, Poland
| | - Sergio Comincini
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
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13
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Li B, Yang Z, Zhao X, Chen Y, Li D, Zhang L, Min H, Yu W, Shen M. Early onset drusen and RPE dysfunction in a patient with NLRP3-AID. Ocul Immunol Inflamm 2023; 31:1877-1880. [PMID: 36395369 DOI: 10.1080/09273948.2022.2113804] [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: 04/05/2022] [Accepted: 08/11/2022] [Indexed: 11/18/2022]
Abstract
Retinal pigment epithelium (RPE) dysfunction, manifested as drusen formation and RPE mottling, is a characteristic lesion of aging. The mechanism of RPE dysfunction remains unknown. Previous animal studies have proven that the activation of NLRP3 inflammasome in RPE leads to apoptosis and pyroptosis, which may play a very important role in the development of age-related macular degeneration (AMD). However, there is a lack of clinical evidence to support the above hypothesis. Herein, we report a 38-year-old Chinese Han woman who had NLRP3-associated autoinflammatory disease (NLRP3-AID) with widely scattered drusen at the posterior pole in both eyes. NLRP3-AID is a rare disease caused by mutations of the NLRP3 gene, leading to NLRP3 inflammasome activation. This report of early-onset drusen provides clinical evidence that the NLRP3 inflammasome might contribute to the occurrence of RPE dysfunction and is a potential cause of age-related macular degeneration (AMD).
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Affiliation(s)
- Bing Li
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Zhikun Yang
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Xufeng Zhao
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Youxin Chen
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Donghui Li
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Li Zhang
- Department of Rheumatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, Hebei, China
| | - Hanyi Min
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Weihong Yu
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, Hebei, China
| | - Min Shen
- Department of Rheumatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, Hebei, China
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14
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Chatterjee A, Singh R. Extracellular vesicles: an emerging player in retinal homeostasis. Front Cell Dev Biol 2023; 11:1059141. [PMID: 37181750 PMCID: PMC10166895 DOI: 10.3389/fcell.2023.1059141] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Abstract
Extracellular vesicles (EVs) encompass secreted membrane vesicles of varied sizes, including exosomes (-30-200 nm) and microvesicles (MVs) that are ∼100-1,000 nm in size. EVs play an important role in autocrine, paracrine, and endocrine signaling and are implicated in myriad human disorders including prominent retinal degenerative diseases, like age related macular degeneration (AMD) and diabetic retinopathy (DR). Studies of EVs in vitro using transformed cell lines, primary cultures, and more recently, induced pluripotent stem cell derived retinal cell type(s) (e.g., retinal pigment epithelium) have provided insights into the composition and function of EVs in the retina. Furthermore, consistent with a causal role of EVs in retinal degenerative diseases, altering EV composition has promoted pro-retinopathy cellular and molecular events in both in vitro and in vivo models. In this review, we summarize the current understanding of the role of EVs in retinal (patho)physiology. Specifically, we will focus on disease-associated EV alterations in specific retinal diseases. Furthermore, we discuss the potential utility of EVs in diagnostic and therapeutic strategies for targeting retinal diseases.
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Affiliation(s)
- Amit Chatterjee
- Department of Ophthalmology, University of Rochester, Rochester, NY, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, NY, United States
- Center for Visual Science, University of Rochester, Rochester, NY, United States
| | - Ruchira Singh
- Department of Ophthalmology, University of Rochester, Rochester, NY, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, NY, United States
- Center for Visual Science, University of Rochester, Rochester, NY, United States
- UR Stem Cell and Regenerative Medicine Center, University of Rochester, Rochester, NY, United States
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15
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Erwin N, Serafim MF, He M. Enhancing the Cellular Production of Extracellular Vesicles for Developing Therapeutic Applications. Pharm Res 2023; 40:833-853. [PMID: 36319886 DOI: 10.1007/s11095-022-03420-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/15/2022] [Indexed: 04/26/2023]
Abstract
Extracellular vesicles (EVs) have various advantageous properties, including a small size, high biocompatibility, efficient cargo loading, and precise cell targeting ability, making them promising tools for therapeutic development. EVs have been increasingly explored for applications like drug delivery. However, due to limited cellular secretion rates of EVs, wide-scale clinical applications are not achievable. Therefore, substantial strategies and research efforts have been devoted to increasing cellular secretion rates of EVs. This review describes various studies exploring different methods to increase the cellular production of EVs, including the application of electrical stimulus, pharmacologic agents, electromagnetic waves, sound waves, shear stress, cell starvation, alcohol, pH, heat, and genetic manipulation. These methods have shown success in increasing EV production, but careful consideration must be given as many of these strategies may alter EV properties and functionalities, and the exact mechanisms causing the increase in cellular production of EVs is generally unknown. Additionally, the methods' effectiveness in increasing EV secretion may diverge with different cell lines and conditions. Further advancements to enhance EV biogenesis secretion for therapeutic development is still a significant need in the field.
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Affiliation(s)
- Nina Erwin
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA
| | - Maria Fernanda Serafim
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA
| | - Mei He
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610, USA.
- UF Cancer and Genetics Research Complex, 2033 Mowry Rd, Lab: 0475G, Gainesville, FL, 32608, USA.
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16
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Shekari F, Abyadeh M, Meyfour A, Mirzaei M, Chitranshi N, Gupta V, Graham SL, Salekdeh GH. Extracellular Vesicles as reconfigurable therapeutics for eye diseases: Promises and hurdles. Prog Neurobiol 2023; 225:102437. [PMID: 36931589 DOI: 10.1016/j.pneurobio.2023.102437] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 03/14/2023] [Indexed: 03/17/2023]
Abstract
A large number of people worldwide suffer from visual impairment. However, most available therapies rely on impeding the development of a particular eye disorder. Therefore, there is an increasing demand for effective alternative treatments, specifically regenerative therapies. Extracellular vesicles, including exosomes, ectosomes, or microvesicles, are released by cells and play a potential role in regeneration. Following an introduction to EV biogenesis and isolation methods, this integrative review provides an overview of our current knowledge about EVs as a communication paradigm in the eye. Then, we focused on the therapeutic applications of EVs derived from conditioned medium, biological fluid, or tissue and highlighted some recent developments in strategies to boost the innate therapeutic potential of EVs by loading various kinds of drugs or being engineered at the level of producing cells or EVs. Challenges faced in the development of safe and effective translation of EV-based therapy into clinical settings for eye diseases are also discussed to pave the road toward reaching feasible regenerative therapies required for eye-related complications.
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Affiliation(s)
- Faezeh Shekari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | | | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mirzaei
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Sydney, NSW, Australia
| | - Nitin Chitranshi
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Sydney, NSW, Australia
| | - Vivek Gupta
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Sydney, NSW, Australia
| | - Stuart L Graham
- Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Sydney, NSW, Australia
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17
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Habibi A, Zarei-Behjani Z, Falamarzi K, Malekpour M, Ebrahimi F, Soleimani M, Nejabat M, Khosravi A, Moayedfard Z, Pakbaz S, Dehdari Ebrahimi N, Azarpira N. Extracellular vesicles as a new horizon in the diagnosis and treatment of inflammatory eye diseases: A narrative review of the literature. Front Immunol 2023; 14:1097456. [PMID: 36969177 PMCID: PMC10033955 DOI: 10.3389/fimmu.2023.1097456] [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: 11/13/2022] [Accepted: 02/14/2023] [Indexed: 03/11/2023] Open
Abstract
Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term "inflammatory eye diseases" refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles' and exosomes' pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.
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Affiliation(s)
- Azam Habibi
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Zarei-Behjani
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kimia Falamarzi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Malekpour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Ebrahimi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masood Soleimani
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Nejabat
- Department of Ophthalmology School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Khosravi
- Department of Ophthalmology School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Pathology, University of Toronto, Toronto, ON, Canada
| | | | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Feng X, Peng Z, Yuan L, Jin M, Hu H, Peng X, Wang Y, Zhang C, Luo Z, Liao H. Research progress of exosomes in pathogenesis, diagnosis, and treatment of ocular diseases. Front Bioeng Biotechnol 2023; 11:1100310. [PMID: 36761297 PMCID: PMC9902372 DOI: 10.3389/fbioe.2023.1100310] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/10/2023] [Indexed: 01/26/2023] Open
Abstract
Exosomes are natural extracellular vesicles with a diameter of 30-150 nm, which exist in biological fluids and contain biomolecules related to the parent cell, such as proteins, nucleic acids, lipids, etc. It has a wide range of biological functions, and participates in the regulation of important physiological and pathological activities of the body. It can be used as a biomarker for early diagnosis of ocular diseases, a potential therapeutic target, a targeted drug carrier, and has a high potential for clinical application. In this paper, we summarized the genesis mechanism, biological functions, research and application progress of exosomes, focused on the engineering strategy of exosomes, and summarized the advantages and disadvantages of common engineering exosome preparation methods. Systematically combed the role of exosomes in corneal diseases, glaucoma, and retinal diseases, to provide a reference for further understanding of the role of exosomes in the pathogenesis, diagnosis, and treatment of ocular diseases. Finally, we further summarized the opportunities and challenges of exosomes for precision medicine. The extension of exosome research to the field of ophthalmology will help advance current diagnostic and therapeutic methods. Tiny exosomes have huge potential.
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Affiliation(s)
- Xinting Feng
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhen Peng
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
- Department of Sports Medicine, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Lingyi Yuan
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
| | - Ming Jin
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
| | - Haijian Hu
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
| | - Xin Peng
- College of Fine Arts, Jiangxi Science and Technology Normal University, Nanchang, China
| | - Yaohua Wang
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
| | - Chun Zhang
- Department of ophthalmology, West China hospital, Sichuan University, Chengdu, China
| | - Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Hongfei Liao
- Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Affiliated Eye Hospital of Nanchang University, Jiangxi Research Institute of Ophthalmology and Visual Science, Nanchang, China
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19
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Calpain-2 Facilitates Autophagic/Lysosomal Defects and Apoptosis in ARPE-19 Cells and Rats Induced by Exosomes from RPE Cells under NaIO 3 Stimulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:3310621. [PMID: 36703913 PMCID: PMC9873447 DOI: 10.1155/2023/3310621] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 10/07/2022] [Accepted: 12/31/2022] [Indexed: 01/19/2023]
Abstract
Although accumulated evidence supports the notion that calpain contributes to eye disease, the mechanisms by which calpain promotes RPE injury are not defined. The present study is aimed at investigating whether the effect of NaIO3-exos (exosomes derived from RPE cells under NaIO3 stimulation) on the dysfunction of the autophagy-lysosomal pathway (ALP) and apoptosis is based on its regulation of calpain activation in ARPE-19 cells and rats. The results showed that calpain-2 activation, ALP dysfunction, and apoptosis were induced by NaIO3-exos in ARPE-19 cells. NaIO3-exo significantly increased autophagic substrates by activating lysosomal dysfunction. ALP dysfunction and apoptosis in vitro could be eliminated by knocking down calpain-2 (si-C2) or the inhibitor calpain-2-IN-1. Further studies indicated that NaIO3-exo enhanced calpain-2 expression, ALP dysfunction, apoptosis, and retinal damage in rats. In summary, these results demonstrate for the first time that calpain-2 is one of the key players in the NaIO3-exo-mediated ALP dysfunction, apoptosis, and retinal damage and identify calpain-2 as a promising target for therapies aimed at age-related macular degeneration (AMD).
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20
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Louie HH, Mugisho OO, Chamley LW, Rupenthal ID. Extracellular Vesicles as Biomarkers and Therapeutics for Inflammatory Eye Diseases. Mol Pharm 2023; 20:23-40. [PMID: 36332193 DOI: 10.1021/acs.molpharmaceut.2c00414] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Extracellular vesicles (EVs) are a group of cell-derived membrane vesicles of varying sizes that can be secreted by most cells. Depending on the type of cell they are derived from, EVs may contain a variety of cargo including proteins, lipids, miRNA, and DNA. Functionally, EVs play important roles in physiological and pathological processes through intercellular communication. While there has already been significant literature on the involvement of EVs in neurological and cardiovascular disease as well as cancer, recent evidence suggests that EVs may also play a role in mediating inflammatory eye diseases. This paper summarizes current advancements in ocular EV research as well as new ways by which EVs may be utilized as novel biomarkers of or therapeutics for inflammatory eye diseases.
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Affiliation(s)
- Henry H Louie
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.,Hub for Extracellular Vesicle Investigations, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Odunayo O Mugisho
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Lawrence W Chamley
- Hub for Extracellular Vesicle Investigations, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.,Department of Obstetrics & Gynaecology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Ilva D Rupenthal
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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21
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Cioanca AV, Natoli R, Wooff Y. Proteomics of Retinal Extracellular Vesicles: A Review into an Unexplored Mechanism in Retinal Health and AMD Pathogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1415:87-94. [PMID: 37440019 DOI: 10.1007/978-3-031-27681-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
Extracellular vesicles (EV) are nanosized delivery vehicles that participate in cell-to-cell communication through the selective transfer of molecular materials including RNA, DNA, lipids, and proteins. In the retina, the role of EV proteins is largely unclear, in part due to the lack of studies and the depth of proteomic analyses of EV cargo. This review summarizes the existing knowledge on retinal EV proteins and provides a comparative reanalysis of existing retinal EV proteomic datasets. Collective findings highlight that in homeostasis, the protein components of neural retinal and RPE-derived EV largely reflect the function of the host cells, while in disease RPE-EV protein composition becomes altered, favoring inflammatory modulation and potentially contributing to drusen formation. While these studies shed light on the potential roles of EV proteins in the neural retina and RPE, it is clear that comprehensive proteomic and molecular studies are required, in particular using in vivo models of retinal degenerations.
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Affiliation(s)
- Adrian V Cioanca
- John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
- The School of Medicine and Psychology, The Australian National University, Canberra, ACT, Australia
| | - Riccardo Natoli
- John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
- The School of Medicine and Psychology, The Australian National University, Canberra, ACT, Australia
| | - Yvette Wooff
- John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
- The School of Medicine and Psychology, The Australian National University, Canberra, ACT, Australia.
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22
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Di Vito Nolfi M, Vecchiotti D, Flati I, Verzella D, Di Padova M, Alesse E, Capece D, Zazzeroni F. EV-Mediated Chemoresistance in the Tumor Microenvironment: Is NF-κB a Player? Front Oncol 2022; 12:933922. [PMID: 35814425 PMCID: PMC9257640 DOI: 10.3389/fonc.2022.933922] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022] Open
Abstract
Drug resistance is a major impediment to patient survival and remains the primary cause of unsuccessful cancer therapy. Drug resistance occurs in many tumors and is frequently induced by chemotherapy which triggers a defensive response both in cancerous and cancer-associated cells that constitute the tumor microenvironment (TME). Cell to cell communication within the TME is often mediated by extracellular vesicles (EVs) which carry specific tumor-promoting factors able to activate survival pathways and immune escape mechanisms, thus sustaining tumor progression and therapy resistance. NF-κB has been recognized as a crucial player in this context. NF-κB activation is involved in EVs release and EVs, in turn, can trigger NF-κB pathway activation in specific contexts, based on secreting cytotype and their specific delivered cargo. In this review, we discuss the role of NF-κB/EVs interplay that sustain chemoresistance in the TME by focusing on the molecular mechanisms that underlie inflammation, EVs release, and acquired drug resistance.
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Affiliation(s)
| | | | | | | | | | | | - Daria Capece
- *Correspondence: Francesca Zazzeroni, ; Daria Capece,
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23
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Duncan RS, Hurtado DT, Hall CW, Koulen P. Differential Mechanisms of Action and Efficacy of Vitamin E Components in Antioxidant Cytoprotection of Human Retinal Pigment Epithelium. Front Pharmacol 2022; 12:798938. [PMID: 35058783 PMCID: PMC8764263 DOI: 10.3389/fphar.2021.798938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 12/21/2022] Open
Abstract
The purpose of this study was to determine if different vitamin E components exhibit similar efficacy and mechanism of action in protecting Retinal pigment epithelium (RPE) cells from oxidative damage. We hypothesized that α-tocopherol (αT) is unique among vitamin E components in its cytoprotective mechanism of action against oxidative stress in RPE cells and that it requires protein synthesis for optimal antioxidant effect. We used cell viability assays, fluorescent chemical labeling of DNA and actin and immuno-labeling of the antioxidant proteins Nrf2 and Sod2 and of the tight junction protein, ZO-1, and confocal microscopy to determine the effects of αT and γT against oxidative stress in immortalized human RPE cells (hTERT-RPE). Using the four main vitamin E components, αT, γT, δ-tocopherol (δT) and α-tocotrienol (αTr), we ascertained that they exhibit similar, but not identical, antioxidant activity as αT when used at equimolar concentrations. In addition, we determined that the exposure time of RPE cells to α-tocopherol is critical for its ability to protect against oxidative damage. Lastly, we determined that αT, but not γT, partially requires the synthesis of new proteins within a 24-h period and prior to exposure to tBHP for optimal cytoprotection. We conclude that, unlike γT and δT, αT appears to be unique in its requirement for transport and/or signaling for it to be an effective antioxidant. As a result, more focus should be paid to which vitamin E components are used for antioxidant interventions.
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Affiliation(s)
- R Scott Duncan
- Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Daniel T Hurtado
- Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Conner W Hall
- Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
| | - Peter Koulen
- Vision Research Center, Department of Ophthalmology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States.,Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, United States
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24
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Mugisho OO, Green CR. The NLRP3 inflammasome in age-related eye disease: Evidence-based connexin hemichannel therapeutics. Exp Eye Res 2021; 215:108911. [PMID: 34958779 DOI: 10.1016/j.exer.2021.108911] [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: 08/30/2021] [Revised: 11/25/2021] [Accepted: 12/21/2021] [Indexed: 12/21/2022]
Abstract
The inflammasome pathway is a fundamental component of the innate immune system, playing a key role especially in chronic age-related eye diseases (AREDs). The inflammasome is of particular interest because it is a common disease pathway that once instigated, can amplify and perpetuate itself leading to chronic inflammation. With aging, it becomes more difficult to shut down inflammation after an insult but the common pathway means that a shared solution may be feasible that could be effective across multiple disease indications. This review focusses on the NLRP3 inflammasome, the most studied and characterized inflammasome in the eye. It describes the two-step signalling required for NLRP3 inflammasome complex activation, and provides evidence for its role in AREDs. In the final section, the article gives an overview of potential NLRP3 inflammasome targeting therapies, before presenting evidence for connexin hemichannel regulators as upstream blockers of inflammasome activation. These have shown therapeutic efficacy in multiple ocular disease models.
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Affiliation(s)
- Odunayo O Mugisho
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
| | - Colin R Green
- Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, New Zealand
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25
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Zhang Y, Jiao Y, Li X, Gao S, Zhou N, Duan J, Zhang M. Pyroptosis: A New Insight Into Eye Disease Therapy. Front Pharmacol 2021; 12:797110. [PMID: 34925047 PMCID: PMC8678479 DOI: 10.3389/fphar.2021.797110] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/15/2021] [Indexed: 02/05/2023] Open
Abstract
Pyroptosis is a lytic form of programmed cell death mediated by gasdermins (GSDMs) with pore-forming activity in response to certain exogenous and endogenous stimuli. The inflammasomes are intracellular multiprotein complexes consisting of pattern recognition receptors, an adaptor protein ASC (apoptosis speck-like protein), and caspase-1 and cause autocatalytic activation of caspase-1, which cleaves gasdermin D (GSDMD), inducing pyroptosis accompanied by cytokine release. In recent years, the pathogenic roles of inflammasomes and pyroptosis in multiple eye diseases, including keratitis, dry eyes, cataracts, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy, have been continuously confirmed. Inhibiting inflammasome activation and abnormal pyroptosis in eyes generally attenuates inflammation and benefits prognosis. Therefore, insight into the pathogenesis underlying pyroptosis and inflammasome development in various types of eye diseases may provide new therapeutic strategies for ocular disorders. Inhibitors of pyroptosis, such as NLRP3, caspase-1, and GSDMD inhibitors, have been proven to be effective in many eye diseases. The purpose of this article is to illuminate the mechanism underlying inflammasome activation and pyroptosis and emphasize its crucial role in various ocular disorders. In addition, we review the application of pyroptosis modulators in eye diseases.
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Affiliation(s)
- Yun Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Jiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Li
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Sheng Gao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Nenghua Zhou
- Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jianan Duan
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
| | - Meixia Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.,Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, China
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26
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Exosomes, extracellular vesicles and the eye. Exp Eye Res 2021; 214:108892. [PMID: 34896308 DOI: 10.1016/j.exer.2021.108892] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/11/2021] [Accepted: 12/06/2021] [Indexed: 12/18/2022]
Abstract
Exosomes are a subset of extracellular vesicles which accommodate a cargo of bioactive biomolecules that generally includes proteins, nucleic acids, lipids, sugars, and related conjugates depicting the cellular environment and are known to mediate a wide array of biological functions, like cellular communication, cellular differentiation, immunomodulation, neovascularization, and cellular waste management. The exponential implication of exosomes in the pathological development and progression of various disorders including neurodegenerative diseases, cardiovascular diseases, and cancer has offered a tremendous opportunity for exploring their role in ocular conditions. Ocular diseases such as age-related macular disease, glaucoma, infectious endophthalmitis, diabetic retinopathy, autoimmune uveitis etc face various challenges in their early diagnosis and treatments due to contributing factors such as delay in the onset of symptoms, microbial identification, difficulty in obtaining samples for biopsy or being diagnosed as masquerade syndromes. Studies have reported unique exosomal cargos that are involved in successful delivery of miRNA or proteins to recipient cells to express desired expression or exploited as a diagnostic marker for various diseases. Furthermore, engineered exosomes can be used for targeted delivery of therapeutics and exosomes being natural nanoparticles found in all types of cells, host may not elicit an immune response against it. With the rapid advancement of opting personalized therapeutics, extending exosomal research to sight-threatening ocular infections can possibly advance the current diagnostic and therapeutic approaches. This review briefs about the current knowledge of exosomes in visual systems, advancements in exosomal and ophthalmic research, participation of exosomes in the pathogenesis of common ocular diseases, the challenges for exosomal therapies along with the future of this promising domain of research for diseases that fatally threaten billions of people worldwide.
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27
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Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H. Biomedicines 2021; 9:biomedicines9070763. [PMID: 34209418 PMCID: PMC8301356 DOI: 10.3390/biomedicines9070763] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/28/2021] [Accepted: 06/28/2021] [Indexed: 12/16/2022] Open
Abstract
Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood-retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD.
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28
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Zhang Z, Liang X, Zhou J, Meng M, Gao Y, Yi G, Fu M. Exosomes in the pathogenesis and treatment of ocular diseases. Exp Eye Res 2021; 209:108626. [PMID: 34087205 DOI: 10.1016/j.exer.2021.108626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 05/09/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022]
Abstract
Exosomes have diverse functions and rich content and are involved in intercellular communication, immune regulation, viral infection, tissue regeneration, and the occurrence, development and metastasis of tumours. Notably, various stem cell-derived exosomes are expected to become new therapeutic approaches for inflammatory diseases and tumours and have good clinical application prospects. However, few studies have examined exosomes in ophthalmic diseases. Therefore, based on the functions of exosomes, this paper summarizes progress in the possible use of exosomes as treatment for specific ophthalmic diseases, aiming to determine the pathogenesis of exosomes to achieve more effective clinical diagnosis and treatment of these diseases.
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Affiliation(s)
- Zhihan Zhang
- Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaotian Liang
- Southern Medical University, Guangzhou, Guangdong, China
| | - Jing Zhou
- Southern Medical University, Guangzhou, Guangdong, China
| | - Meijun Meng
- Southern Medical University, Guangzhou, Guangdong, China
| | - Ya Gao
- Southern Medical University, Guangzhou, Guangdong, China
| | - Guoguo Yi
- Department of Ophthalmology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Min Fu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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29
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Zhang Z, Mugisha A, Fransisca S, Liu Q, Xie P, Hu Z. Emerging Role of Exosomes in Retinal Diseases. Front Cell Dev Biol 2021; 9:643680. [PMID: 33869195 PMCID: PMC8049503 DOI: 10.3389/fcell.2021.643680] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/05/2021] [Indexed: 12/12/2022] Open
Abstract
Retinal diseases, the leading causes of vison loss and blindness, are associated with complicated pathogeneses such as angiogenesis, inflammation, immune regulation, fibrous proliferation, and neurodegeneration. The retina is a complex tissue, where the various resident cell types communicate between themselves and with cells from the blood and immune systems. Exosomes, which are bilayer membrane vesicles with diameters of 30–150 nm, carry a variety of proteins, lipids, and nucleic acids, and participate in cell-to-cell communication. Recently, the roles of exosomes in pathophysiological process and their therapeutic potential have been emerging. Here, we critically review the roles of exosomes as possible intracellular mediators and discuss the possibility of using exosomes as therapeutic agents in retinal diseases.
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Affiliation(s)
- Zhengyu Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Aime Mugisha
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Silvia Fransisca
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Xie
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zizhong Hu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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30
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Noonin C, Thongboonkerd V. Exosome-inflammasome crosstalk and their roles in inflammatory responses. Am J Cancer Res 2021; 11:4436-4451. [PMID: 33754070 PMCID: PMC7977448 DOI: 10.7150/thno.54004] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammasome is a complex of multiple proteins found in cytoplasm of the cells activated by infectious and/or non-infectious stimuli. This complex involves caspase-1 activation, leading to unconventional secretion of interleukin-1β (IL-1β) and IL-18 and inflammatory cascade. Exosome is the nanoscale membrane-bound extracellular vesicle that plays significant roles in intercellular communications by carrying bioactive molecules, e.g., proteins, RNAs, microRNAs (miRNAs), DNAs, from one cell to the others. In this review, we provide the update information on the crosstalk between exosome and inflammasome and their roles in inflammatory responses. The effects of inflammasome activation on exosomal secretion are summarized. On the other hand, the (dual) effects of exosomes on inhibiting and promoting inflammasome activation are discussed. Finally, perspectives on therapeutic roles of exosomes in human diseases and future direction of the research on exosome-inflammasome crosstalk are provided.
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31
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Li Y, Jin R, Li L, Choi JS, Kim J, Yoon HJ, Park JH, Yoon KC. Blue Light Induces Impaired Autophagy through Nucleotide-Binding Oligomerization Domain 2 Activation on the Mouse Ocular Surface. Int J Mol Sci 2021; 22:2015. [PMID: 33670592 PMCID: PMC7922400 DOI: 10.3390/ijms22042015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 02/06/2021] [Indexed: 12/12/2022] Open
Abstract
In this study, we investigated the effects of blue light exposure on nucleotide-binding oligomerization domain 2 (NOD2) expression on the mouse ocular surface and evaluated the role of NOD2 activation in light-induced cell death. Mice were divided into wild-type (WT), NOD2-knock out (KO), WT + blue light (WT + BL), and NOD2-KO + blue light (NOD2-KO + BL) groups, and the mice in the WT+BL and NOD2-KO + BL groups were exposed to blue light for 10 days. After 10 days of blue light exposure, increased reactive oxygen species and malondialdehyde were observed in the WT + BL and NOD2-KO + BL groups, and the WT + BL group showed a higher expression of NOD2 and autophagy related 16 like 1. Although both WT+BL and NOD2-KO + BL groups showed an increase in the expression of light chain 3-II, NOD2-KO + BL mice had a significantly lower p62 expression than WT + BL mice. In addition, NOD2-KO+BL mice had significantly lower corneal epithelial damage and apoptosis than WT + BL mice. In conclusion, blue light exposure can induce impaired autophagy by activation of NOD2 on the ocular surface. In addition, the reactive oxygen species (ROS)-NOD2-autophagy related 16 like 1 (ATG16L) signaling pathway may be involved in the blue-light-induced autophagy responses, resulting in corneal epithelial apoptosis.
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Affiliation(s)
- Ying Li
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Rujun Jin
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Lan Li
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
- Department of Biomedical Sciences and Centers for Creative Biomedical Scientists, Chonnam National University, Gwangju 61469, Korea
| | - Ji Suk Choi
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Jonghwa Kim
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Hyeon Jeong Yoon
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
| | - Jong Hwan Park
- Laboratory of Animal Medicine, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 77, Korea;
| | - Kyung Chul Yoon
- Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea; (Y.L.); (R.J.); (L.L.); (J.S.C.); (J.K.); (H.J.Y.)
- Department of Biomedical Sciences and Centers for Creative Biomedical Scientists, Chonnam National University, Gwangju 61469, Korea
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32
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Wooff Y, Cioanca AV, Chu-Tan JA, Aggio-Bruce R, Schumann U, Natoli R. Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy. Front Cell Neurosci 2020; 14:160. [PMID: 32670023 PMCID: PMC7330137 DOI: 10.3389/fncel.2020.00160] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Photoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases such as age-related macular degeneration (AMD). However, the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs, including exosomes, encapsulate and transfer microRNA (miRNA) to recipient cells and in this way can modulate the environment of recipient cells. Dysregulation of EVs however is correlated to a loss of cellular homeostasis and increased inflammation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina. Isolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion. Results demonstrated an inverse correlation between s-mEV concentration and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue, however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage. Taken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.
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Affiliation(s)
- Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,The ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Adrian V Cioanca
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Joshua A Chu-Tan
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,The ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,The ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Ulrike Schumann
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,The ANU Medical School, The Australian National University, Canberra, ACT, Australia
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33
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Zhang W, Jiang H, Kong Y. Exosomes derived from platelet-rich plasma activate YAP and promote the fibrogenic activity of Müller cells via the PI3K/Akt pathway. Exp Eye Res 2020; 193:107973. [PMID: 32059976 DOI: 10.1016/j.exer.2020.107973] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 02/09/2020] [Accepted: 02/11/2020] [Indexed: 12/16/2022]
Abstract
The purpose of this study was to investigate the role of exosomes derived from platelet-rich plasma (PRP-Exos) in the regulation of the fibrogenic activity of Müller cells and the underlying mechanism. We studied the effects of PRP-Exos on the fibrogenic activity of human retinal Müller cells (hMCs) in vitro. PRP-Exos were isolated from the plasma of diabetic rats (DM-PRP-Exos) and normal control rats (Nor-PRP-Exos) and then observed by transmission electron microscopy. After treatment with DM-PRP-Exos or Nor-PRP-Exos, the proliferation and migration of hMCs were measured in vitro. Western blotting was conducted to assess the levels of fibrogenic molecules and activation of Yes-associated protein (YAP) and the PI3K-Akt signalling pathway. In cultured hMCs, DM-PRP-Exos but not Nor-PRP-Exos effectively increased the proliferative and migratory activities and improved connective tissue growth factor (CTGF) and fibronectin expression. Genetic and pharmacological suppression of YAP could reduce the proliferative and migratory activities of hMCs induced by DM-PRP-Exo. Additionally, YAP knockdown inhibited the DM-PRP-Exo-induced up-regulation of CTGF and fibronectin. Furthermore, DM-PRP-Exo-induced PI3K-Akt signalling mediated YAP activation and the expression of CTGF and fibronectin. In summary, DM-PRP-Exos, through YAP activation, enhance both the proliferation and fibrogenic activity of Müller cells via the PI3K/Akt pathway.
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Affiliation(s)
- Wei Zhang
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, 300020, China
| | - Hao Jiang
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, 300020, China
| | - Yichun Kong
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, 300020, China.
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34
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Lim RR, Wieser ME, Ganga RR, Barathi VA, Lakshminarayanan R, Mohan RR, Hainsworth DP, Chaurasia SS. NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy. Int J Mol Sci 2020; 21:E899. [PMID: 32019187 PMCID: PMC7037099 DOI: 10.3390/ijms21030899] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/22/2020] [Accepted: 01/27/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.
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Affiliation(s)
- Rayne R. Lim
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
| | - Margaret E. Wieser
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
| | - Rama R. Ganga
- Surgery, University of Missouri, Columbia, MO 652011, USA;
| | | | | | - Rajiv R. Mohan
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA;
| | - Dean P. Hainsworth
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 652011, USA;
| | - Shyam S. Chaurasia
- Ocular Immunology and Angiogenesis Lab, University of Missouri, Columbia, MO 652011, USA; (R.R.L.); (M.E.W.); (R.R.M.)
- Department of Biomedical Sciences, University of Missouri, Columbia, MO 652011, USA
- Ophthalmology, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 652011, USA
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35
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Fluent MT, Ferracane JL, Mace JG, Shah AR, Price RB. Shedding light on a potential hazard: Dental light-curing units. J Am Dent Assoc 2019; 150:1051-1058. [PMID: 31761019 DOI: 10.1016/j.adaj.2019.08.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/23/2019] [Accepted: 08/06/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Dental light-curing units (LCUs) are powerful sources of blue light that can cause soft-tissue burns and ocular damage. Although most ophthalmic research on the hazards of blue light pertains to low levels from personal electronic devices, computer monitors, and light-emitting diode light sources, the amount of blue light emitted from dental LCUs is much greater and may pose a "blue light hazard." METHODS The authors explain the potential risks of using dental LCUs, identify the agencies that provide guidelines designed to protect all workers from excessive exposure to blue light, discuss the selection of appropriate eye protection, and provide clinical tips to ensure eye safety when using LCUs. RESULTS While current literature and regulatory standards regarding the safety of blue light is primarily based on animal studies, sufficient evidence exists to suggest that appropriate precautions should be taken when using dental curing lights. The authors found it difficult to find on the U.S. Food and Drug Administration database which curing lights had been cleared for use in the United States or Europe and could find no database that listed which brands of eyewear designed to protect against the blue light has been cleared for use. The authors conclude that more research is needed on the cumulative exposure to blue light in humans. Manufacturers of curing lights, government and regulatory agencies, employers, and dental personnel should collaborate to determine ocular risks from blue light exist in the dental setting, and recommend appropriate eye protection. Guidance on selection and proper use of eye protection should be readily accessible. CONCLUSIONS AND PRACTICAL IMPLICATIONS The Centers for Disease Control and Prevention Guidelines for Infection Control in the Dental Health-Care Setting-2003 and the Occupational Safety and Health Administration Bloodborne Pathogen Standard do not include safety recommendations or regulations that are directly related to blue light exposure. However, there are additional Occupational Safety and Health Administration regulations that require employers to protect their employees from potentially injurious light radiation. Unfortunately, it is not readily evident that these regulations apply to the excessive exposure to blue light. Consequently employers and dental personnel may be unaware that these Occupational Safety and Health Administration regulations exist.
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Mechanisms of extracellular vesicle uptake in stressed retinal pigment epithelial cell monolayers. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165608. [PMID: 31740401 DOI: 10.1016/j.bbadis.2019.165608] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/24/2019] [Accepted: 11/05/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Extracellular vesicles (EVs) can mediate long-distance communication in polarized RPE monolayers. Specifically, EVs from oxidatively stressed donor cells (stress EVs) rapidly reduced barrier function (transepithelial resistance, TER) in naïve recipient monolayers, when compared to control EVs. This effect on TER was dependent on dynamin-mediated EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Here, we further determined molecular mechanisms involved in uptake of EVs by naïve RPE cells. METHODS RPE cells were grown as monolayers in media supplemented with 1% FBS followed by transfer to FBS-free media. Cultures were used to collect control or stress EVs upon treatment with H2O2, others served as naïve recipient cells. In recipient monolayers, TER was used to monitor EV-uptake-based activity, live-cell imaging confirmed uptake. EV surface proteins were quantified by protein chemistry. RESULTS Clathrin-independent, lipid raft-mediated internalization was excluded as an uptake mechanism. Known ligand-receptor interactions involved in clathrin-dependent endocytosis include integrins and proteoglycans. Desialylated glycans and integrin-receptors on recipient cells were necessary for EV uptake and subsequent reduction of TER in recipient cells. Protein quantifications confirmed elevated levels of ligands and neuraminidase on stress EVs. However, control EVs could confer activity in the TER assay if exogenous neuraminidase or additional ligand was provided. CONCLUSIONS In summary, while EVs from both stressed cells and control contain cargo to communicate stress messages to naive RPE cells, stress EVs contain surface ligands that confer rapid uptake by recipient cells. We propose that EVs potentially contribute to RPE dysfunction in aging and disease.
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Zhang W, Dong X, Wang T, Kong Y. Exosomes derived from platelet-rich plasma mediate hyperglycemia-induced retinal endothelial injury via targeting the TLR4 signaling pathway. Exp Eye Res 2019; 189:107813. [PMID: 31560926 DOI: 10.1016/j.exer.2019.107813] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 09/01/2019] [Accepted: 09/23/2019] [Indexed: 01/07/2023]
Abstract
In this study, we aimed to investigate whether exosomes derived from platelet-rich plasma (PRP-Exos) can regulate hyperglycemia-induced retinal injury via targeting the TLR4 signaling pathway. We studied the effects of PRP-Exos on retinal endothelial injury in diabetic rats and human retinal endothelial cells (HRECs) in vitro. Isolated PRP-Exos were observed by transmission electron microscopy and flow cytometry. Samples were obtained from the retinas of rats and cultured HRECs after treatment to analyze reactive oxygen species levels. Immunofluorescence and Western blotting were conducted to assess the levels of adhesion molecules and the TLR4 signaling pathway. The content of CXCL10 in PRP-Exos was analyzed by Western blot. The plasma level of PRP-Exos was greatly increased in diabetic rats. In cultured HRECs, PRP-Exos induced the production of malonyldialdehyde(MDA) and reactive oxygen species(ROS) and inhibited the activity of superoxide dismutase(SOD). Further analysis showed that the activation of the TLR4 pathway by PRP-Exos played a pivotal role in regulating inflammation. The inhibition of the TLR4 pathway by TAK-242 had a robust protective effect on PRP-Exo-induced retinal endothelial injury in vitro and vivo. In addition, PRP-Exo-derived CXCL10 led to retinal endothelial injury, and antagonizing CXCL10 with a CXCL10-neutralizing antibody dramatically attenuated such injury. In summary, PRP-Exos mediate hyperglycemia-induced retinal endothelial injury by upregulating the TLR4 signaling pathway.
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Affiliation(s)
- Wei Zhang
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, 300020, China
| | - Xue Dong
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Tian Wang
- Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yichun Kong
- Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, 300020, China.
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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: 170] [Impact Index Per Article: 28.3] [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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Interplay between Autophagy and the Ubiquitin-Proteasome System and Its Role in the Pathogenesis of Age-Related Macular Degeneration. Int J Mol Sci 2019; 20:ijms20010210. [PMID: 30626110 PMCID: PMC6337628 DOI: 10.3390/ijms20010210] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 12/21/2018] [Accepted: 01/02/2019] [Indexed: 12/20/2022] Open
Abstract
Age-related macular degeneration (AMD) is a complex eye disease with many pathogenesis factors, including defective cellular waste management in retinal pigment epithelium (RPE). Main cellular waste in AMD are: all-trans retinal, drusen and lipofuscin, containing unfolded, damaged and unneeded proteins, which are degraded and recycled in RPE cells by two main machineries—the ubiquitin-proteasome system (UPS) and autophagy. Recent findings show that these systems can act together with a significant role of the EI24 (etoposide-induced protein 2.4 homolog) ubiquitin ligase in their action. On the other hand, E3 ligases are essential in both systems, but E3 is degraded by autophagy. The interplay between UPS and autophagy was targeted in several diseases, including Alzheimer disease. Therefore, cellular waste clearing in AMD should be considered in the context of such interplay rather than either of these systems singly. Aging and oxidative stress, two major AMD risk factors, reduce both UPS and autophagy. In conclusion, molecular mechanisms of UPS and autophagy can be considered as a target in AMD prevention and therapeutic perspective. Further work is needed to identify molecules and effects important for the coordination of action of these two cellular waste management systems.
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