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Talwar S, Harker JA, Openshaw PJM, Thwaites RS. Autoimmunity in long COVID. J Allergy Clin Immunol 2025; 155:1082-1094. [PMID: 39956285 DOI: 10.1016/j.jaci.2025.02.005] [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: 11/25/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 02/18/2025]
Abstract
Long COVID (also termed postacute sequelae of SARS-CoV-2, or PASC) affects up to 10% of people recovering from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnosis is hampered by diffuse symptomatology, lack of biomarkers, incomplete understanding of pathogenesis, and lack of validated treatments. In terms of pathogenesis, hypothesized causes include virus persistence, the legacy of endotheliitis and thrombosis, low-grade tissue-based inflammation and/or scarring, perturbation of the host virome/microbiome, or triggering of autoimmunity. Several studies show preexisting and/or de novo production of autoantibodies after infection with SARS-CoV-2, but the persistence of these antibodies and their role in causing long COVID is debated. Here, we review the mechanisms through which autoimmune responses can arise during and after viral infection, focusing on the evidence for B-cell dysregulation and autoantibody production in acute and long COVID.
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Affiliation(s)
- Shubha Talwar
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - James A Harker
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Peter J M Openshaw
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Ryan S Thwaites
- National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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2
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Magnusen AF, Pandey MK. Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int J Mol Sci 2024; 25:12252. [PMID: 39596318 PMCID: PMC11594573 DOI: 10.3390/ijms252212252] [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: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Manoj Kumar Pandey
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
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Maffia P, Mauro C, Case A, Kemper C. Canonical and non-canonical roles of complement in atherosclerosis. Nat Rev Cardiol 2024; 21:743-761. [PMID: 38600367 DOI: 10.1038/s41569-024-01016-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/18/2024] [Indexed: 04/12/2024]
Abstract
Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Pasquale Maffia
- School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Africa-Europe Cluster of Research Excellence (CoRE) in Non-Communicable Diseases & Multimorbidity, African Research Universities Alliance (ARUA) & The Guild, Accra, Ghana
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Ayden Case
- Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.
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Wolf HN, Guempelein L, Schikora J, Pauly D. C3a Mediates Endothelial Barrier Disruption in Brain-Derived, but Not Retinal, Human Endothelial Cells. Int J Mol Sci 2024; 25:11240. [PMID: 39457022 PMCID: PMC11508547 DOI: 10.3390/ijms252011240] [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: 09/05/2024] [Revised: 10/11/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is associated with pathological aquaporin-4 immunoglobulin G (AQP4-IgG), which cause brain damage. However, the impact of AQP4-IgG on retinal tissue remains unclear. Additionally, dysregulated complement anaphylatoxins C3a and C5a, known to modulate the endothelial barrier, are implicated in NMOSD. This study evaluates the susceptibility of human brain microvascular endothelial cells (HBMEC) and human retinal endothelial cells (HREC) to C3a- and C5a-mediated stress using real-time cell barrier analysis, immunocytochemical staining, qPCR and IgG transmigration assays. The findings reveal that C3a induced a concentration-dependent paracellular barrier breakdown and increased transcellular permeability in HBMEC, while HREC maintained barrier integrity under the same conditions. C5a attenuated C3a-induced disruption in HBMEC, indicating a protective role. Anaphylatoxin treatment elevated transcript levels of complement component C3 and increased C5 gene and protein expression in HREC, with no changes observed in HBMEC. In HBMEC, C5a treatment led to a transient upregulation of C3a receptor (C3AR) mRNA and an early decrease in C5a receptor 1 (C5AR1) protein detection. Conversely, HREC exhibited a late increase in C5aR1 protein levels. These results indicate that the retinal endothelial barrier is more stable under anaphylatoxin-induced stress compared to the brain, potentially offering better protection against paracellular AQP4-IgG transport.
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Affiliation(s)
| | | | | | - Diana Pauly
- Department of Experimental Ophthalmology, University Marburg, 35043 Marburg, Germany
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Mrozewski L, Tharmalingam S, Michael P, Kumar A, Tai TC. C5a Induces Inflammatory Signaling and Apoptosis in PC12 Cells through C5aR-Dependent Signaling: A Potential Mechanism for Adrenal Damage in Sepsis. Int J Mol Sci 2024; 25:10673. [PMID: 39409001 PMCID: PMC11477224 DOI: 10.3390/ijms251910673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/28/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
The complement system is critically involved in the pathogenesis of sepsis. In particular, complement anaphylatoxin C5a is generated in excess during sepsis, leading to cellular dysfunction. Recent studies have shown that excessive C5a impairs adrenomedullary catecholamine production release and induces apoptosis in adrenomedullary cells. Currently, the mechanisms by which C5a impacts adrenal cell function are poorly understood. The PC12 cell model was used to examine the cellular effects following treatment with recombinant rat C5a. The levels of caspase activation and cell death, protein kinase signaling pathway activation, and changes in inflammatory protein expression were examined following treatment with C5a. There was an increase in apoptosis of PC12 cells following treatment with high-dose C5a. Ten inflammatory proteins, primarily involved in apoptosis, cell survival, and cell proliferation, were upregulated following treatment with high-dose C5a. Five inflammatory proteins, involved primarily in chemotaxis and anti-inflammatory functions, were downregulated. The ERK/MAPK, p38/MAPK, JNK/MAPK, and AKT protein kinase signaling pathways were upregulated in a C5aR-dependent manner. These results demonstrate an apoptotic effect and cellular signaling effect of high-dose C5a. Taken together, the overall data suggest that high levels of C5a may play a role in C5aR-dependent apoptosis of adrenal medullary cells in sepsis.
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Affiliation(s)
- Lucas Mrozewski
- School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada; (L.M.); (S.T.); (P.M.); (A.K.)
| | - Sujeenthar Tharmalingam
- School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada; (L.M.); (S.T.); (P.M.); (A.K.)
- Medical Science Division, NOSM University, Sudbury, ON P3E 2C6, Canada
| | - Paul Michael
- School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada; (L.M.); (S.T.); (P.M.); (A.K.)
| | - Aseem Kumar
- School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada; (L.M.); (S.T.); (P.M.); (A.K.)
- Medical Science Division, NOSM University, Sudbury, ON P3E 2C6, Canada
| | - T. C. Tai
- School of Natural Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada; (L.M.); (S.T.); (P.M.); (A.K.)
- Medical Science Division, NOSM University, Sudbury, ON P3E 2C6, Canada
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Finzi A, Ottoboni S, Cellini M, Corcioni B, Gaudiano C, Fontana L. Color Doppler Imaging, Endothelin-1, Corneal Biomechanics and Scleral Rigidity in Asymmetric Age-Related Macular Degeneration. Clin Ophthalmol 2024; 18:2583-2591. [PMID: 39281979 PMCID: PMC11401527 DOI: 10.2147/opth.s479225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/02/2024] [Indexed: 09/18/2024] Open
Abstract
Purpose Age-related macular degeneration (AMD) presents a multifaceted etiopathogenesis involving ischemic, inflammatory, and genetic components. This study investigates the correlation between ocular hemodynamics, scleral rigidity (SR), and plasma endothelin-1 (ET1) levels in treatment-naive patients with asymmetrical AMD. Patients and Methods This study included 20 treatment-naive patients (12 females and 8 males) with an average age of 76.4 ± 3.7 years, who presented with AMD with neovascular membrane formation (nAMD) in one eye, and intermediate grade 2 AMD (iAMD) in the other eye. The control group consisted of 20 healthy subjects (13 females and 7 males) with a mean age of 74.7 ± 3.9 years. All patients and healthy controls underwent color Doppler imaging (i) of the ophthalmic artery (OA), short posterior ciliary arteries (SPCAs), and central retinal artery (CRA); Plasma ET-1 levels were measured for all patients and healthy subjects. Corneal biomechanics were assessed using an Ocular Response Analyzer and two indices were obtained: corneal hysteresis (CH) and corneal resistance factor (CRF). Results Results showed reduced blood flow velocities and increased resistance indices in AMD eyes, particularly affecting the short posterior ciliary arteries. According to mechanical theory, ARMD eyes exhibited elevated scleral rigidity and corneal resistance factor compared to controls, with a notable rise in SR in neovascular AMD (nAMD) eyes. As per the chronic subacute inflammation theory, plasma ET-1 levels were significantly higher in AMD patients, correlating with abnormal SPCAs blood flow and increased resistance indices. Conclusion Findings suggest a multifactorial etiology of AMD involving an increase of ET-1 plasma levels with biomechanic damages of corneal and scleral tissue in nAMD.
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Affiliation(s)
- Alessandro Finzi
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Simone Ottoboni
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Mauro Cellini
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Beniamino Corcioni
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Caterina Gaudiano
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luigi Fontana
- Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Zabihi MR, Farhadi B, Akhoondian M. Complement protein expression changes in various conditions of breast cancer: in-silico analyses-experimental research. Ann Med Surg (Lond) 2024; 86:5152-5161. [PMID: 39239051 PMCID: PMC11374204 DOI: 10.1097/ms9.0000000000002216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 05/15/2024] [Indexed: 09/07/2024] Open
Abstract
Introduction Breast cancer is the most prevalent cancer diagnosed in females worldwide. The known biomarkers are insufficient to understand the actual prognosis of breast cancer, and identifying new biomarkers is desirable and valuable data to improve the patient's survival. Many inflammatory biomarkers, such as the complement system, can be regarded as prognostic values and as potent inflammatory mediators; complement proteins have a critical role in tumorigenesis. In the current study, the authors aim to investigate complement protein expression changes, particularly complement 3 (C3), complement 7 (C7), complement factor B (CFB), and complement factor D (CFD), in various conditions of breast cancer using in-silico tools. Methods The intent data were extracted using webtools, including; Kaplan-Meier plotter, BcGenExMiner, UALCAN, cbioportal, GeneMania, and Enrichr. To select valid data, a P greater than 0.05 was considered. Results The current study clarified that 21 complement genes correlated to survival conditions. Also, down or upregulation of extracted genes and breast cancer statuses were identified. Additionally, expression level difference of complement genes in various breast cancer four stages was detected. Ultimately, co-expression genes with complement genes were extracted and networked. Conclusion Changes in the expression of complement proteins can strongly correlate to breast cancer's prognosis, status, and survival. Furthermore, considering the vital role of CFD and CFB complement proteins in the alternative pathway in different stages of breast cancer, CFD and CFB can be regarded as reliable prognostic values for diagnosis.
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Affiliation(s)
- Mohammad Reza Zabihi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences
| | - Bahar Farhadi
- School of Medicine, Islamic Azad University, Mashhad Branch, Mashhad
| | - Mohammad Akhoondian
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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8
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O’Brien JW, Case A, Kemper C, Zhao TX, Mallat Z. Therapeutic Avenues to Modulate B-Cell Function in Patients With Cardiovascular Disease. Arterioscler Thromb Vasc Biol 2024; 44:1512-1522. [PMID: 38813699 PMCID: PMC11208059 DOI: 10.1161/atvbaha.124.319844] [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] [Indexed: 05/31/2024]
Abstract
The adaptive immune system plays an important role in the development and progression of atherosclerotic cardiovascular disease. B cells can have both proatherogenic and atheroprotective roles, making treatments aimed at modulating B cells important therapeutic targets. The innate-like B-cell response is generally considered atheroprotective, while the adaptive response is associated with mixed consequences for atherosclerosis. Additionally, interactions of B cells with components of the adaptive and innate immune system, including T cells and complement, also represent key points for therapeutic regulation. In this review, we discuss therapeutic approaches based on B-cell depletion, modulation of B-cell survival, manipulation of both the antibody-dependent and antibody-independent B-cell response, and emerging immunization techniques.
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Affiliation(s)
- James W. O’Brien
- Division of Cardiorespiratory Medicine, Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, United Kingdom (J.W.O., A.C., T.X.Z., Z.M.)
| | - Ayden Case
- Division of Cardiorespiratory Medicine, Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, United Kingdom (J.W.O., A.C., T.X.Z., Z.M.)
| | - Claudia Kemper
- Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (C.K.)
| | - Tian X. Zhao
- Division of Cardiorespiratory Medicine, Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, United Kingdom (J.W.O., A.C., T.X.Z., Z.M.)
- Department of Cardiology, Royal Papworth Hospital, Cambridge, United Kingdom (T.X.Z.)
| | - Ziad Mallat
- Division of Cardiorespiratory Medicine, Department of Medicine, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, United Kingdom (J.W.O., A.C., T.X.Z., Z.M.)
- Unversité de Paris, Inserm U970, Paris Cardiovascular Research Centre, France (Z.M.)
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Hristodorov D, Lohoff T, Luneborg N, Mulder GJ, Clark SJ. Investing in vision: Innovation in retinal therapeutics and the influence on venture capital investment. Prog Retin Eye Res 2024; 99:101243. [PMID: 38218527 DOI: 10.1016/j.preteyeres.2024.101243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/15/2024]
Abstract
Since the groundbreaking approval of the first anti-VEGF therapy in 2004, the retinal therapeutics field has undergone a remarkable transformation, witnessing a surge in novel, disease-modifying therapeutics for a broad spectrum of retinal diseases, extending beyond exudative VEGF-driven conditions. The surge in scientific advancement and the pressing, unmet, medical need have captured the attention of venture capital investors, who have collectively invested close to $10 billion in research and development of new retinal therapeutics between 2004 and 2023. Notably, the field of exudative diseases has gradually shifted away from trying to outcompete anti-VEGF therapeutics towards lowering the overall treatment burden by reducing injection frequency. Simultaneously, a new era has emerged in the non-exudative field, targeting prevalent conditions like dry AMD and rare indications such as Retinitis pigmentosa. This has led to promising drug candidates in development, culminating in the landmark approval of Luxturna for a rare form of Retinitis pigmentosa. The validation of new mechanisms, such as the complement pathway in dry AMD has paved the way for the approvals of Syvovre (Apellis) and Izervay (Iveric/Astellas), marking the first two therapies for this condition. In this comprehensive review, we share our view on the cumulative lessons from the past two decades in developing retinal therapeutics, covering both positive achievements and challenges. We also contextualize the investments, strategic partnering deals, and acquisitions of biotech companies, pharmaceutical companies venture capital investors in retinal therapeutics, respectively. Finally, we provide an outlook and potentially a forward-looking roadmap on novel retinal therapeutics, highlighting the emergence of potential new intervention strategies, such as cell-based therapies, gene editing, and combination therapies. We conclude that upcoming developments have the potential to further stimulate venture capital investments, which ultimately could facilitate the development and delivery of new therapies to patients in need.
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Affiliation(s)
| | | | | | | | - Simon J Clark
- Institute for Ophthalmic Research, Department for Ophthalmology, University Medical Center, Eberhard Karls University of Tübingen, Tübingen, Germany; University Eye Clinic, University Hospital Tübingen, Tübingen, Germany; Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK
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Abdolrahimzadeh S, Zweifel SA, Di Pippo M, Bajka A, Scuderi G, Lotery AJ. Central macular choriocapillaris impairment as a manifestation of microvascular disease in eyes with subretinal drusenoid deposits. Eye (Lond) 2024; 38:173-178. [PMID: 37419959 PMCID: PMC10764916 DOI: 10.1038/s41433-023-02654-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/09/2023] Open
Abstract
BACKGROUND/OBJECTIVES Microvascular alterations and choroidal impairment are emerging as a pathologic pathway in age-related macular degeneration (AMD). This study aimed to evaluate the central macular choriocapillaris (CC) in eyes with subretinal drusenoid deposits (SDD) and the retinal microvasculature in patients with early AMD phenotypes. SUBJECTS/METHODS This was an institutional, multicentric observational cross-sectional study. Ninety-nine eyes of 99 subjects; 33 eyes with SDD only, 33 eyes with conventional drusen (CD) only, and 33 eyes of healthy age-matched subjects were included. Comprehensive ophthalmologic examination and optical coherence tomography angiography (OCTA) was performed. The central macular flow area of the CC was analysed in the SDD group and the vessel density of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) was analysed in the SDD and CD groups using automated OCTA output parameters. RESULTS The flow area of the CC in the SDD group was significantly reduced (p ≤ 0.001) with respect to the healthy control group. There was a trend of reduction of vessel density of the SCP and the DCP in the SDD and CD group with respect to controls, although this did not reach statistical significance. CONCLUSIONS OCTA data in the present report corroborate the role of vascular damage in early AMD with CC impairment in the central macular area in eyes with SDD.
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Affiliation(s)
- Solmaz Abdolrahimzadeh
- Ophthalmology Unit, Neurosciences, Mental Health, and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, University of Rome Sapienza, Rome, Italy.
- St. Andrea Hospital, Via di Grottarossa 1035/1039, Rome, Italy.
| | - Sandrine Anne Zweifel
- Department of Ophthalmology, University Hospital Zurich (USZ), University of Zurich, Zurich, Switzerland
| | - Mariachiara Di Pippo
- Ophthalmology Unit, Neurosciences, Mental Health, and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, University of Rome Sapienza, Rome, Italy
| | - Anahita Bajka
- Department of Ophthalmology, University Hospital Zurich (USZ), University of Zurich, Zurich, Switzerland
| | - Gianluca Scuderi
- Ophthalmology Unit, Neurosciences, Mental Health, and Sense Organs (NESMOS) Department, Faculty of Medicine and Psychology, University of Rome Sapienza, Rome, Italy
- St. Andrea Hospital, Via di Grottarossa 1035/1039, Rome, Italy
| | - Andrew John Lotery
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
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Berlin A, Messinger JD, Ramtohul P, Balaratnasingam C, Mendis R, Ferrara D, Freund KB, Curcio CA. INFLAMMATORY CELL ACTIVITY IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Histologic Case Study. Retina 2023; 43:1904-1913. [PMID: 37871271 PMCID: PMC10801910 DOI: 10.1097/iae.0000000000003881] [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] [Indexed: 07/27/2023]
Abstract
BACKGROUND Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.
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Affiliation(s)
- Andreas Berlin
- Department of Ophthalmology and Visual Sciences, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham AL, USA
- Department of Ophthalmology, University Hospital Würzburg, Würzburg, Germany
| | - Jeffrey D Messinger
- Department of Ophthalmology and Visual Sciences, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham AL, USA
| | | | - Chandrakumar Balaratnasingam
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
- Lions Eye Institute, Nedlands, Western Australia, Australia
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Western Australia, Australia
| | | | | | - K. Bailey Freund
- Vitreous Retina Macula Consultants of New York NY, USA
- Department of Ophthalmology, New York University Grossman School of Medicine, New York NY, USA
| | - Christine A Curcio
- Department of Ophthalmology and Visual Sciences, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham AL, USA
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Ioannou M, Fella E, Papacharalambous R, Kynigopoulos D, Panayiotou E. Treatment of the CRND8 mouse model for cerebral amyloid angiopathy, exhibited increased levels of neuron specific enolase in brain tissue following long-term treatment with a modified C5a receptor agonist, accompanied by improved cognitive function. Biochem Biophys Res Commun 2023; 675:78-84. [PMID: 37454400 DOI: 10.1016/j.bbrc.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/07/2023] [Accepted: 07/01/2023] [Indexed: 07/18/2023]
Abstract
Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy (CAA). CAA is a condition manifesting as amyloid deposits in the cerebral vasculature, eventually leading to microhemorrhage. Here, we have treated the CRND8 mouse model with the C5a agonist (EP67) in order to observe the effects on cerebral amyloidosis, CAA, and hyperphosphorylated tau. EP67 attaches to the C5a receptor on phagocytes and stimulates the engulfment and digestion of fibrillar and prefibrillar amyloid while exhibiting minimal inflammation. Older CRND8 mice and their respective controls were treated with EP67 for a prolonged period of time. Following treatment, the CRND8 mice displayed improved spatial memory, while both amyloid deposition and tau hyperphosphorylation were found to be diminished.
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Affiliation(s)
- Maria Ioannou
- Neuropathology Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Eleni Fella
- Neuropathology Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | | | - Demos Kynigopoulos
- Neuropathology Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Elena Panayiotou
- Neuropathology Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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13
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Huang X, Zhang L, Fu Y, Zhang M, Yang Q, Peng J. Rethinking the potential and necessity of drug delivery systems in neovascular age-related macular degeneration therapy. Front Bioeng Biotechnol 2023; 11:1199922. [PMID: 37288355 PMCID: PMC10242387 DOI: 10.3389/fbioe.2023.1199922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/09/2023] [Indexed: 06/09/2023] Open
Abstract
Age-related macular degeneration (AMD) is the predominant threat to human vision and ultimately results in blindness. With the increase in the aging population, it has become a more crucial issue to human health. AMD is a multifactorial disease with the unique feature of uncontrollable angiogenesis during initiation and progression. Although increasing evidence indicates that AMD is largely hereditary, the predominant efficient treatment is antiangiogenesis, which mainly involves VEGF and HIF-α as therapeutic targets. The repeated administration of this treatment over the long term, generally through intravitreal injection, has called for the introduction of long-term drug delivery systems, which are expected to be achieved by biomaterials. However, the clinical results of the port delivery system indicate that the optimization of medical devices toward prolonging the activities of therapeutic biologics in AMD therapy seems more promising. These results indicate that we should rethink the possibility and potential of biomaterials as drug delivery systems in achieving long-term, sustained inhibition of angiogenesis in AMD therapy. In this review, the etiology, categorization, risk factors, pathogenesis, and current clinical treatments of AMD are briefly introduced. Next, the development status of long-term drug delivery systems is discussed, and the drawbacks and shortages of these systems are emphasized. By comprehensively considering the pathological aspect and the recent application of drug delivery systems in AMD therapy, we hope to find a better solution for the further development of long-term therapeutic strategies for AMD.
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Affiliation(s)
- Xi Huang
- Department of Ophthalmology, Research Laboratory of Macular Disease, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Zhang
- Department of Ophthalmology, Research Laboratory of Macular Disease, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanyan Fu
- Department of Ophthalmology, Research Laboratory of Macular Disease, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Meixia Zhang
- Department of Ophthalmology, Research Laboratory of Macular Disease, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qian Yang
- Center of Scientific Research, Chengdu Medical College, Chengdu, Sichuan, China
| | - Jinrong Peng
- Department of Ophthalmology, Research Laboratory of Macular Disease, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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14
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Hammadi S, Tzoumas N, Ferrara M, Meschede IP, Lo K, Harris C, Lako M, Steel DH. Bruch's Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration. J Clin Med 2023; 12:2870. [PMID: 37109207 PMCID: PMC10145879 DOI: 10.3390/jcm12082870] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
The complement system is crucial for immune surveillance, providing the body's first line of defence against pathogens. However, an imbalance in its regulators can lead to inappropriate overactivation, resulting in diseases such as age-related macular degeneration (AMD), a leading cause of irreversible blindness globally affecting around 200 million people. Complement activation in AMD is believed to begin in the choriocapillaris, but it also plays a critical role in the subretinal and retinal pigment epithelium (RPE) spaces. Bruch's membrane (BrM) acts as a barrier between the retina/RPE and choroid, hindering complement protein diffusion. This impediment increases with age and AMD, leading to compartmentalisation of complement activation. In this review, we comprehensively examine the structure and function of BrM, including its age-related changes visible through in vivo imaging, and the consequences of complement dysfunction on AMD pathogenesis. We also explore the potential and limitations of various delivery routes (systemic, intravitreal, subretinal, and suprachoroidal) for safe and effective delivery of conventional and gene therapy-based complement inhibitors to treat AMD. Further research is needed to understand the diffusion of complement proteins across BrM and optimise therapeutic delivery to the retina.
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Affiliation(s)
- Sarah Hammadi
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Nikolaos Tzoumas
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Sunderland Eye Infirmary, Queen Alexandra Rd., Sunderland SR2 9H, UK
| | | | - Ingrid Porpino Meschede
- Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK
| | - Katharina Lo
- Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK
| | - Claire Harris
- Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK
- Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Majlinda Lako
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - David H. Steel
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
- Sunderland Eye Infirmary, Queen Alexandra Rd., Sunderland SR2 9H, UK
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15
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Santos FM, Ciordia S, Mesquita J, Cruz C, Sousa JPCE, Passarinha LA, Tomaz CT, Paradela A. Proteomics profiling of vitreous humor reveals complement and coagulation components, adhesion factors, and neurodegeneration markers as discriminatory biomarkers of vitreoretinal eye diseases. Front Immunol 2023; 14:1107295. [PMID: 36875133 PMCID: PMC9978817 DOI: 10.3389/fimmu.2023.1107295] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/01/2023] [Indexed: 02/18/2023] Open
Abstract
Introduction Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of visual impairment and blindness in people aged 50 years or older in middle-income and industrialized countries. Anti-VEGF therapies have improved the management of neovascular AMD (nAMD) and proliferative DR (PDR), no treatment options exist for the highly prevalent dry form of AMD. Methods To unravel the biological processes underlying these pathologies and to find new potential biomarkers, a label-free quantitative (LFQ) method was applied to analyze the vitreous proteome in PDR (n=4), AMD (n=4) compared to idiopathic epiretinal membranes (ERM) (n=4). Results and discussion Post-hoc tests revealed 96 proteins capable of differentiating among the different groups, whereas 118 proteins were found differentially regulated in PDR compared to ERM and 95 proteins in PDR compared to dry AMD. Pathway analysis indicates that mediators of complement, coagulation cascades and acute phase responses are enriched in PDR vitreous, whilst proteins highly correlated to the extracellular matrix (ECM) organization, platelet degranulation, lysosomal degradation, cell adhesion, and central nervous system development were found underexpressed. According to these results, 35 proteins were selected and monitored by MRM (multiple reaction monitoring) in a larger cohort of patients with ERM (n=21), DR/PDR (n=20), AMD (n=11), and retinal detachment (n=13). Of these, 26 proteins could differentiate between these vitreoretinal diseases. Based on Partial least squares discriminant and multivariate exploratory receiver operating characteristic (ROC) analyses, a panel of 15 discriminatory biomarkers was defined, which includes complement and coagulation components (complement C2 and prothrombin), acute-phase mediators (alpha-1-antichymotrypsin), adhesion molecules (e.g., myocilin, galectin-3-binding protein), ECM components (opticin), and neurodegeneration biomarkers (beta-amyloid, amyloid-like protein 2).
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Affiliation(s)
- Fátima M. Santos
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
| | - Sergio Ciordia
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
| | - Joana Mesquita
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Carla Cruz
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Chemistry Department, Faculty of Sciences, University of Beira Interior, Covilhã, Portugal
| | - João Paulo Castro e Sousa
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Luís A. Passarinha
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculdade de Ciências e Tecnologia, Universidade NOVA, Caparica, Portugal
- UCIBIO–Applied Molecular Biosciences Unit, Departamento de Química/Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal
- Laboratório de Fármaco-Toxicologia, UBIMedical, Universidade da Beira Interior, Covilhã, Portugal
| | - Cândida T. Tomaz
- CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
- Chemistry Department, Faculty of Sciences, University of Beira Interior, Covilhã, Portugal
| | - Alberto Paradela
- Functional Proteomics Laboratory, Centro Nacional de Biotecnología, CSIC, Madrid, Spain
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16
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Abstract
The complement and hemostatic systems are complex systems, and both involve enzymatic cascades, regulators, and cell components-platelets, endothelial cells, and immune cells. The two systems are ancestrally related and are defense mechanisms that limit infection by pathogens and halt bleeding at the site of vascular injury. Recent research has uncovered multiple functional interactions between complement and hemostasis. On one side, there are proteins considered as complement factors that activate hemostasis, and on the other side, there are coagulation proteins that modulate complement. In addition, complement and coagulation and their regulatory proteins strongly interact each other to modulate endothelial, platelet and leukocyte function and phenotype, creating a potentially devastating amplifying system that must be closely regulated to avoid unwanted damage and\or disseminated thrombosis. In view of its ability to amplify all complement activity through the C3b-dependent amplification loop, the alternative pathway of complement may play a crucial role in this context. In this review, we will focus on available and emerging evidence on the role of the alternative pathway of complement in regulating hemostasis and vice-versa, and on how dysregulation of either system can lead to severe thromboinflammatory events.
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Affiliation(s)
- Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Miriam Galbusera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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17
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Freda CT, Yin W, Ghebrehiwet B, Rubenstein DA. Complement component C1q initiates extrinsic coagulation via the receptor for the globular head of C1q in adventitial fibroblasts and vascular smooth muscle cells. Immun Inflamm Dis 2023; 11:e769. [PMID: 36705413 PMCID: PMC9868878 DOI: 10.1002/iid3.769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Vascular diseases are highly associated with inflammation and thrombosis. Elucidating links between these two processes may provide a clearer understanding of these diseases, allowing for the design of more effective treatments. The activation of complement component 1 (C1) is a crucial contributor to innate immunity and is associated with significant concentrations of circulating C1q. Many pathological pathways initiate when C1q interacts with gC1qR. This interaction plays a major role in inflammation observed during atherosclerosis and the initiation of intrinsic coagulation. However, the effects of C1 and the role of C1q/gC1qR on extrinsic coagulation, which is the more physiologically relevant coagulation arm, has not been studied. We hypothesized that C1q binding to gC1qR enhances the expression of tissue factor (TF) in adventitial fibroblasts and vascular smooth muscle cells, the primary TF bearing cells in the body. METHODS Using an enzyme-linked immunosorbent assay approach, TF expression and the role of gC1qR was observed. Cells were conditioned for 1 h with C1q or a gC1qR blocker and C1q, to assess the role of gC1qR. Additionally, cell growth characteristics were monitored to assess changes in viability and metabolic activity. RESULTS Our results indicate that the expression of TF increased significantly after incubation with C1q as compared with unconditioned cells. Cells conditioned with gC1qR blockers and C1q exhibited no change in TF expression when compared with cells conditioned with the blocking antibodies alone. Our results show no significant differences in metabolic activity or cell viability under these conditions. CONCLUSIONS This indicates that gC1qR association with C1q induces TF expression and may initiate extrinsic coagulation. Overall, this data illustrates a role for C1q in the activation of extrinsic coagulation and that gC1qR activity may link inflammation and thrombosis.
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Affiliation(s)
- Christopher T. Freda
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
| | - Wei Yin
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
| | | | - David A. Rubenstein
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew YorkUSA
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18
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Alfaar AS, Stürzbecher L, Diedrichs-Möhring M, Lam M, Roubeix C, Ritter J, Schumann K, Annamalai B, Pompös IM, Rohrer B, Sennlaub F, Reichhart N, Wildner G, Strauß O. FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration. J Neuroinflammation 2022; 19:260. [PMID: 36273134 PMCID: PMC9588251 DOI: 10.1186/s12974-022-02620-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 10/09/2022] [Indexed: 11/15/2022] Open
Abstract
Background Forkhead-Box-Protein P3 (FoxP3) is a transcription factor and marker of regulatory T cells, converting naive T cells into Tregs that can downregulate the effector function of other T cells. We previously detected the expression of FoxP3 in retinal pigment epithelial (RPE) cells, forming the outer blood–retina barrier of the immune privileged eye. Methods We investigated the expression, subcellular localization, and phosphorylation of FoxP3 in RPE cells in vivo and in vitro after treatment with various stressors including age, retinal laser burn, autoimmune inflammation, exposure to cigarette smoke, in addition of IL-1β and mechanical cell monolayer destruction. Eye tissue from humans, mouse models of retinal degeneration and rats, and ARPE-19, a human RPE cell line for in vitro experiments, underwent immunohistochemical, immunofluorescence staining, and PCR or immunoblot analysis to determine the intracellular localization and phosphorylation of FoxP3. Cytokine expression of stressed cultured RPE cells was investigated by multiplex bead analysis. Depletion of the FoxP3 gene was performed with CRISPR/Cas9 editing. Results RPE in vivo displayed increased nuclear FoxP3-expression with increases in age and inflammation, long-term exposure of mice to cigarette smoke, or after laser burn injury. The human RPE cell line ARPE-19 constitutively expressed nuclear FoxP3 under non-confluent culture conditions, representing a regulatory phenotype under chronic stress. Confluently grown cells expressed cytosolic FoxP3 that was translocated to the nucleus after treatment with IL-1β to imitate activated macrophages or after mechanical destruction of the monolayer. Moreover, with depletion of FoxP3, but not of a control gene, by CRISPR/Cas9 gene editing decreased stress resistance of RPE cells. Conclusion Our data suggest that FoxP3 is upregulated by age and under cellular stress and might be important for RPE function. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02620-w.
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Affiliation(s)
- Ahmad Samir Alfaar
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany.,Department of Ophthalmology, University Hospital of Ulm, 89075, Ulm, Germany
| | - Lucas Stürzbecher
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Maria Diedrichs-Möhring
- Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, 80336, Munich, Germany
| | - Marion Lam
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Christophe Roubeix
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Julia Ritter
- Institut Für Med. Mikrobiologie, Immunologie Und Hygiene, TU München, 81675, Munich, Germany
| | - Kathrin Schumann
- Institut Für Med. Mikrobiologie, Immunologie Und Hygiene, TU München, 81675, Munich, Germany
| | - Balasubramaniam Annamalai
- Department of Ophthalmology, College of Medicine, Medical University South Carolina, Charleston, SC, 29425, USA
| | - Inga-Marie Pompös
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Bärbel Rohrer
- Department of Ophthalmology, College of Medicine, Medical University South Carolina, Charleston, SC, 29425, USA
| | - Florian Sennlaub
- Institut de La Vision, Sorbonne Université, INSERM, CNRS, 75012, Paris, France
| | - Nadine Reichhart
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany
| | - Gerhild Wildner
- Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, 80336, Munich, Germany.
| | - Olaf Strauß
- Experimental Ophthalmology, Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität, Berlin Institute of Health, Humboldt-University, 10117, Berlin, Germany.
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19
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Ma L, Willey J. The interplay between inflammation and thrombosis in COVID-19: Mechanisms, therapeutic strategies, and challenges. THROMBOSIS UPDATE 2022; 8:100117. [PMID: 38620713 PMCID: PMC9270234 DOI: 10.1016/j.tru.2022.100117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/08/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause life-threatening pathology characterized by a dysregulated immune response and coagulopathy. While respiratory failure induced by inflammation is the most common cause of death, micro-and macrovascular thrombosis leading to multiple organ failure are also causes of mortality. Dysregulation of systemic inflammation observed in severe COVID-19 patients is manifested by cytokine release syndrome (CRS) - the aberrant release of high levels of proinflammatory cytokines, such as IL-6, IL-1, TNFα, MP-1, as well as complement. CRS is often accompanied by activation of endothelial cells and platelets, coupled with perturbation of the balance between the pro-and antithrombotic mechanisms, resulting in thrombosis. Inflammation and thrombosis form a vicious circle, contributing to morbidity and mortality. Treatment of hyperinflammation has been shown to decrease thrombosis, while anti-thrombotic treatment also downregulates cytokine release. This review highlights the relationship between COVID-19-mediated systemic inflammation and thrombosis, the molecular pathways involved, the therapies targeting these processes, and the challenges currently encountered.
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Affiliation(s)
- Li Ma
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Joanne Willey
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
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20
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Voigt AP, Mullin NK, Mulfaul K, Lozano LP, Wiley LA, Flamme-Wiese MJ, Boese EA, Han IC, Scheetz TE, Stone EM, Tucker BA, Mullins RF. Choroidal endothelial and macrophage gene expression in atrophic and neovascular macular degeneration. Hum Mol Genet 2022; 31:2406-2423. [PMID: 35181781 PMCID: PMC9307320 DOI: 10.1093/hmg/ddac043] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 01/22/2022] [Accepted: 02/06/2022] [Indexed: 11/22/2022] Open
Abstract
The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on 21 human choroids, 11 of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.
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Affiliation(s)
- Andrew P Voigt
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Nathaniel K Mullin
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Kelly Mulfaul
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Lola P Lozano
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Luke A Wiley
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Miles J Flamme-Wiese
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Erin A Boese
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Ian C Han
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Todd E Scheetz
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Edwin M Stone
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Budd A Tucker
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
| | - Robert F Mullins
- Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA
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21
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Chen J, Du L, Wang F, Shao X, Wang X, Yu W, Bi S, Chen D, Pan X, Zeng S, Huang L, Liang Y, Li Y, Chen R, Xue F, Li X, Wang S, Zhuang M, Liu M, Lin L, Yan H, He F, Yu L, Jiang Q, Xiong Z, Zhang L, Cao B, Wang Y, Chen D. Cellular and molecular atlas of the placenta from a COVID-19 pregnant woman infected at midgestation highlights the defective impacts on foetal health. Cell Prolif 2022; 55:e13204. [PMID: 35141964 PMCID: PMC9055894 DOI: 10.1111/cpr.13204] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/10/2022] [Accepted: 01/26/2022] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES The impacts of the current COVID-19 pandemic on maternal and foetal health are enormous and of serious concern. However, the influence of SARS-CoV-2 infection at early-to-mid gestation on maternal and foetal health remains unclear. MATERIALS AND METHODS Here, we report the follow-up study of a pregnant woman of her whole infective course of SARS-CoV-2, from asymptomatic infection at gestational week 20 to mild and then severe illness state, and finally cured at Week 24. Following caesarean section due to incomplete uterine rupture at Week 28, histological examinations on the placenta and foetal tissues as well as single-cell RNA sequencing (scRNA-seq) for the placenta were performed. RESULTS Compared with the gestational age-matched control placentas, the placenta from this COVID-19 case exhibited more syncytial knots and lowered expression of syncytiotrophoblast-related genes. The scRNA-seq analysis demonstrated impaired trophoblast differentiation, activation of antiviral and inflammatory CD8 T cells, as well as the tight association of increased inflammatory responses in the placenta with complement over-activation in macrophages. In addition, levels of several inflammatory factors increased in the placenta and foetal blood. CONCLUSION These findings illustrate a systematic cellular and molecular signature of placental insufficiency and immune activation at the maternal-foetal interface that may be attributed to SARS-CoV-2 infection at the midgestation stage, which highly suggests the extensive care for maternal and foetal outcomes in pregnant women suffering from COVID-19.
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22
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Park U, Cho NH. Protective and pathogenic role of humoral responses in COVID-19. J Microbiol 2022; 60:268-275. [PMID: 35235178 PMCID: PMC8890013 DOI: 10.1007/s12275-022-2037-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/14/2022] [Accepted: 02/14/2022] [Indexed: 12/24/2022]
Abstract
Since the advent of SARS-CoV-2 in Dec. 2019, the global endeavor to identify the pathogenic mechanism of COVID-19 has been ongoing. Although humoral immunity including neutralizing activity play an important role in protection from the viral pathogen, dysregulated antibody responses may be associated with the pathogenic progression of COVID-19, especially in high-risk individuals. In addition, SARS-CoV-2 spike-specific antibodies acquired by prior infection or vaccination act as immune pressure, driving continuous population turnover by selecting for antibody-escaping mutations. Here, we review accumulating knowledge on the potential role of humoral immune responses in COVID-19, primarily focusing on their beneficial and pathogenic properties. Understanding the multifaceted regulatory mechanisms of humoral responses during SARS-CoV-2 infection can help us to develop more effective therapeutics, as well as protective measures against the ongoing pandemic.
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Affiliation(s)
- Uni Park
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
| | - Nam-Hyuk Cho
- Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
- Institute of Endemic Disease, Seoul National University Medical Research Center, Seoul, 03080, Republic of Korea.
- Seoul National University Bundang Hospital, Seongnam, 13620, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, 25159, Republic of Korea.
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23
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Abstract
Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.
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Affiliation(s)
- Behdad Afzali
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
| | - Marina Noris
- Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Ranica, Italy.
- "Centro Anna Maria Astori", Bergamo, Italy.
| | - Bart N Lambrecht
- Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
- Department of Pulmonary Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
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24
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Aiello S, Gastoldi S, Galbusera M, Ruggenenti P, Portalupi V, Rota S, Rubis N, Liguori L, Conti S, Tironi M, Gamba S, Santarsiero D, Benigni A, Remuzzi G, Noris M. C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. Blood Adv 2022; 6:866-881. [PMID: 34852172 PMCID: PMC8945302 DOI: 10.1182/bloodadvances.2021005246] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/19/2021] [Indexed: 11/20/2022] Open
Abstract
Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.
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Affiliation(s)
- Sistiana Aiello
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Gastoldi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Miriam Galbusera
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Piero Ruggenenti
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Valentina Portalupi
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Stefano Rota
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Nadia Rubis
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Lucia Liguori
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Conti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Matteo Tironi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Sara Gamba
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Donata Santarsiero
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
| | - Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; and
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25
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Chen RC, Palestine AG, Lynch AM, Patnaik JL, Wagner BD, Mathias MT, Mandava N. Increased Systemic C-Reactive Protein Is Associated With Choroidal Thinning in Intermediate Age-Related Macular Degeneration. Transl Vis Sci Technol 2021; 10:7. [PMID: 34609476 PMCID: PMC8496412 DOI: 10.1167/tvst.10.12.7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose C-reactive protein (CRP) and decreased choroidal thickness (CT) are risk factors for progression to advanced age-related macular degeneration (AMD). We examined the association between systemic levels of CRP and CT in patients with intermediate AMD (iAMD). Methods Patients with iAMD in the Colorado AMD Registry were included. Baseline serum samples and multimodal imaging including spectral domain–optical coherence tomography (SD-OCT), fundus photography, and autofluorescence were obtained. Medical and social histories were surveyed. CT was obtained by manual segmentation of OCT images. High-sensitivity CRP levels were quantified in serum samples. Univariate and multivariable linear regression models accounting for the intrasubject correlation of two eyes were fit using log-transformed CT as the outcome. Results The study included 213 eyes from 107 patients with a mean age of 76.8 years (SD, 6.8). Median CT was 200.5 µm (range, 86.5–447.0). Median CRP was 1.43 mg/L (range, 0.13–17.10). Higher CRP was associated with decreased CT in the univariate model (P = 0.01). Older age and presence of reticular pseudodrusen (RPD) were associated with decreased CT (P < 0.01), whereas gender, body mass index, and smoking were not associated with CT. Higher CRP remained significantly associated with decreased CT after adjustment for age and RPD (P = 0.01). Conclusions Increased CRP may damage the choroid, leading to choroidal thinning and increased risk of progression to advanced AMD. Alternatively, CRP may be a marker for inflammatory events that mediate ocular disease. The results of this study further strengthen the association between inflammation and AMD. Translational Relevance Increased CRP is associated with choroidal thinning, a clinical risk factor for AMD.
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Affiliation(s)
- Rachel C Chen
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
| | - Alan G Palestine
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
| | - Anne M Lynch
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
| | - Jennifer L Patnaik
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
| | - Brandie D Wagner
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA.,Department of Biostatistics and Informatics, Colorado School of Public Health, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Marc T Mathias
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
| | - Naresh Mandava
- UCHealth Sue Anschutz-Rodgers Eye Center, University of Colorado, Aurora, CO, USA
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26
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Brinks J, van Dijk EHC, Klaassen I, Schlingemann RO, Kielbasa SM, Emri E, Quax PHA, Bergen AA, Meijer OC, Boon CJF. Exploring the choroidal vascular labyrinth and its molecular and structural roles in health and disease. Prog Retin Eye Res 2021; 87:100994. [PMID: 34280556 DOI: 10.1016/j.preteyeres.2021.100994] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/04/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022]
Abstract
The choroid is a key player in maintaining ocular homeostasis and plays a role in a variety of chorioretinal diseases, many of which are poorly understood. Recent advances in the field of single-cell RNA sequencing have yielded valuable insights into the properties of choroidal endothelial cells (CECs). Here, we review the role of the choroid in various physiological and pathophysiological mechanisms, focusing on the role of CECs. We also discuss new insights regarding the phenotypic properties of CECs, CEC subpopulations, and the value of measuring transcriptomics in primary CEC cultures derived from post-mortem eyes. In addition, we discuss key phenotypic, structural, and functional differences that distinguish CECs from other endothelial cells such as retinal vascular endothelial cells. Understanding the specific clinical and molecular properties of the choroid will shed new light on the pathogenesis of the broad clinical range of chorioretinal diseases such as age-related macular degeneration, central serous chorioretinopathy and other diseases within the pachychoroid spectrum, uveitis, and diabetic choroidopathy. Although our knowledge is still relatively limited with respect to the clinical features and molecular pathways that underlie these chorioretinal diseases, we summarise new approaches and discuss future directions for gaining new insights into these sight-threatening diseases and highlight new therapeutic strategies such as pluripotent stem cell‒based technologies and gene therapy.
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Affiliation(s)
- J Brinks
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - E H C van Dijk
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - I Klaassen
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - R O Schlingemann
- Ocular Angiogenesis Group, Departments of Ophthalmology and Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland
| | - S M Kielbasa
- Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
| | - E Emri
- Department of Clinical Genetics, Section of Ophthalmogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - P H A Quax
- Department of Vascular Surgery, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - A A Bergen
- Department of Clinical Genetics, Section of Ophthalmogenetics, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - O C Meijer
- Department of Medicine, Division of Endocrinology and Metabolism, Leiden University Medical Center, Leiden, the Netherlands
| | - C J F Boon
- Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands; Department of Ophthalmology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
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27
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Kim BJ, Mastellos DC, Li Y, Dunaief JL, Lambris JD. Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions. Prog Retin Eye Res 2021; 83:100936. [PMID: 33321207 PMCID: PMC8197769 DOI: 10.1016/j.preteyeres.2020.100936] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 12/13/2022]
Abstract
Age-related macular degeneration (AMD) remains a major cause of legal blindness, and treatment for the geographic atrophy form of AMD is a significant unmet need. Dysregulation of the complement cascade is thought to be instrumental for AMD pathophysiology. In particular, C3 and C5 are pivotal components of the complement cascade and have become leading therapeutic targets for AMD. In this article, we discuss C3 and C5 in detail, including their roles in AMD, biochemical and structural aspects, locations of expression, and the functions of C3 and C5 fragments. Further, the article critically reviews developing therapeutics aimed at C3 and C5, underscoring the potential effects of broad inhibition of complement at the level of C3 versus more specific inhibition at C5. The relationships of complement biology to the inflammasome and microglia/macrophage activity are highlighted. Concepts of C3 and C5 biology will be emphasized, while we point out questions that need to be settled and directions for future investigations.
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Affiliation(s)
- Benjamin J Kim
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | | | - Yafeng Li
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Joshua L Dunaief
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - John D Lambris
- Department of Laboratory Medicine and Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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28
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Skeie JM, Nishimura DY, Wang CL, Schmidt GA, Aldrich BT, Greiner MA. Mitophagy: An Emerging Target in Ocular Pathology. Invest Ophthalmol Vis Sci 2021; 62:22. [PMID: 33724294 PMCID: PMC7980050 DOI: 10.1167/iovs.62.3.22] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 02/20/2021] [Indexed: 12/16/2022] Open
Abstract
Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.
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Affiliation(s)
- Jessica M. Skeie
- Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
- Iowa Lions Eye Bank, Coralville, Iowa, United States
| | - Darryl Y. Nishimura
- Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
- Iowa Lions Eye Bank, Coralville, Iowa, United States
| | - Cheryl L. Wang
- Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
| | | | - Benjamin T. Aldrich
- Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
- Iowa Lions Eye Bank, Coralville, Iowa, United States
| | - Mark A. Greiner
- Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States
- Iowa Lions Eye Bank, Coralville, Iowa, United States
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29
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Gunawardana H, Romero T, Yao N, Heidt S, Mulder A, Elashoff DA, Valenzuela NM. Tissue-specific endothelial cell heterogeneity contributes to unequal inflammatory responses. Sci Rep 2021; 11:1949. [PMID: 33479269 PMCID: PMC7820348 DOI: 10.1038/s41598-020-80102-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022] Open
Abstract
Endothelial cells (EC) coordinate vascular homeostasis and inflammation. In organ transplantation, EC are a direct alloimmune target. We posited that tissue specific heterogeneity of vascular EC may partly underlie the disparate organ-specific alloimmune risk. We examined the vascular endothelial response to inflammation across six primary endothelial beds from four major transplanted organs: the heart, lung, kidney and liver. First, we reanalyzed a public dataset of cardiac allograft rejection and found that endothelial inflammatory response genes were elevated in human cardiac allograft biopsies undergoing rejection compared with stable grafts. Next, the inducible inflammatory phenotypes of EC from heart, lung, kidney, and liver were characterized in vitro, focused on expression of adhesion molecules and chemokines, and recruitment of allogeneic peripheral blood mononuclear immune cells. Large vessel cardiac EC most highly upregulated VCAM-1, particularly compared with hepatic EC, supported greater leukocyte adhesion and had distinct chemokine profiles after stimulation with cytokines and complement. Differentially expressed gene candidates that are known regulators of cytokine signaling and inflammatory programming were verified in publicly available datasets of organ-specific endothelial transcriptomes. In summary, differential baseline expression of immune regulating genes may contribute to differential vascular inflammatory responses depending on organ.
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Affiliation(s)
- Hasitha Gunawardana
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA
| | - Tahmineh Romero
- Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Ning Yao
- Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Sebastiaan Heidt
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Arend Mulder
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - David A Elashoff
- Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 1-520, Los Angeles, CA, 90095, USA.
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30
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Propson NE, Gedam M, Zheng H. Complement in Neurologic Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:277-298. [PMID: 33234021 DOI: 10.1146/annurev-pathol-031620-113409] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Classic innate immune signaling pathways provide most of the immune response in the brain. This response activates many of the canonical signaling mechanisms identified in peripheral immune cells, despite their relative absence in this immune-privileged tissue. Studies over the past decade have strongly linked complement protein production and activation to age-related functional changes and neurodegeneration. The reactivation of the complement signaling pathway in aging and disease has opened new avenues for understanding brain aging and neurological disease pathogenesis and has implicated cell types such as astrocytes, microglia, endothelial cells, oligodendrocytes, neurons, and even peripheral immune cells in these processes. In this review, we aim to unravel the past decade of research related to complement activation and its numerous consequences in aging and neurological disease.
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Affiliation(s)
- Nicholas E Propson
- Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Manasee Gedam
- Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Hui Zheng
- Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.,Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
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31
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Tzoumas N, Hallam D, Harris CL, Lako M, Kavanagh D, Steel DHW. Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants. Surv Ophthalmol 2020; 66:378-401. [PMID: 33157112 DOI: 10.1016/j.survophthal.2020.10.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022]
Abstract
Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single-nucleotide polymorphism in the complement factor H gene was identified as a major heritable determinant of age-related macular degeneration, galvanizing global efforts to unravel the pathogenesis of this common disease. Advances in proteomic analyses and familial aggregation studies have revealed distinctive clinical phenotypes segregated by the functional effects of common and rare genetic variants on the mature protein and its splice variant, factor H-like protein 1. The predominance of loss-of-function, N-terminal mutations implicate age-related macular degeneration as a disease of general complement dysregulation, offering several therapeutic avenues for its modulation. Here, we explore the molecular impact of these mutations/polymorphisms on the ability of variant factor H/factor H-like protein 1 to localize to polyanions, pentraxins, proinflammatory triggers, and cell surfaces across ocular and renal tissues and exert its multimodal regulatory functions and their clinical implications. Finally, we critically evaluate key therapeutic and diagnostic efforts in this rapidly evolving field.
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Affiliation(s)
- Nikolaos Tzoumas
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
| | - Dean Hallam
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Claire L Harris
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Majlinda Lako
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David Kavanagh
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - David H W Steel
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Sunderland Eye Infirmary, Sunderland, United Kingdom
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32
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Merle NS, Singh P, Rahman J, Kemper C. Integrins meet complement: The evolutionary tip of an iceberg orchestrating metabolism and immunity. Br J Pharmacol 2020; 178:2754-2770. [PMID: 32562277 PMCID: PMC8359198 DOI: 10.1111/bph.15168] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 12/18/2022] Open
Abstract
Immunologists have recently realized that there is more to the classic innate immune sensor systems than just mere protection against invading pathogens. It is becoming increasingly clear that such sensors, including the inflammasomes, toll-like receptors, and the complement system, are heavily involved in the regulation of basic cell physiological processes and particularly those of metabolic nature. In fact, their "non-canonical" activities make sense as no system directing immune cell activity can perform such task without the need for energy. Further, many of these ancient immune sensors appeared early and concurrently during evolution, particularly during the developmental leap from the single-cell organisms to multicellularity, and therefore crosstalk heavily with each other. Here, we will review the current knowledge about the emerging cooperation between the major inter-cell communicators, integrins, and the cell-autonomous intracellularly and autocrine-active complement, the complosome, during the regulation of single-cell metabolism. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Nicolas S Merle
- Complement and Inflammation Research Section (CIRS), National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Parul Singh
- Complement and Inflammation Research Section (CIRS), National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Jubayer Rahman
- Complement and Inflammation Research Section (CIRS), National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Claudia Kemper
- Complement and Inflammation Research Section (CIRS), National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.,Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
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Xie CB, Jane-Wit D, Pober JS. Complement Membrane Attack Complex: New Roles, Mechanisms of Action, and Therapeutic Targets. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1138-1150. [PMID: 32194049 DOI: 10.1016/j.ajpath.2020.02.006] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/24/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
Abstract
The complement membrane attack complex (MAC) is classically known as a cytolytic effector of innate and adaptive immunity that forms pores in the plasma membrane of pathogens or targeted cells, leading to osmolysis. Nucleated cells resist MAC-mediated cytolysis by expression of inhibitors that block MAC assembly or by rapid removal of MAC through endocytosis or shedding. In the absence of lysis, MAC may induce intracellular signaling and cell activation, responses implicated in a variety of autoimmune, inflammatory, and transplant disease settings. New discoveries into the structure and biophysical properties of MAC revealed heterogeneous MAC precursors and conformations that provide insights into MAC function. In addition, new mechanisms of MAC-mediated signaling and its contribution to disease pathogenesis have recently come to light. MAC-activated cells have been found to express proinflammatory proteins-often through NF-κB-dependent transcription, assemble inflammasomes, enabling processing, and facilitate secretion of IL-1β and IL-18, as well as other signaling pathways. These recent insights into the mechanisms of action of MAC provide an updated framework to therapeutic approaches that can target MAC assembly, signaling, and proinflammatory effects in various complement-mediated diseases.
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Affiliation(s)
- Catherine B Xie
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut
| | - Dan Jane-Wit
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Jordan S Pober
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
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McFadyen JD, Zeller J, Potempa LA, Pietersz GA, Eisenhardt SU, Peter K. C-Reactive Protein and Its Structural Isoforms: An Evolutionary Conserved Marker and Central Player in Inflammatory Diseases and Beyond. Subcell Biochem 2020; 94:499-520. [PMID: 32189313 DOI: 10.1007/978-3-030-41769-7_20] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
C-reactive protein (CRP) is an evolutionary highly conserved member of the pentraxin superfamily of proteins. CRP is widely used as a marker of inflammation, infection and for risk stratification of cardiovascular events. However, there is now a large body of evidence, that continues to evolve, detailing that CRP directly mediates inflammatory reactions and the innate immune response in the context of localised tissue injury. These data support the concept that the pentameric conformation of CRP dissociates into pro-inflammatory CRP isoforms termed pCRP* and monomeric CRP. These pro-inflammatory CRP isoforms undergo conformational changes that facilitate complement binding and immune cell activation and therefore demonstrate the ability to trigger complement activation, activate platelets, monocytes and endothelial cells. The dissociation of pCRP occurs on the surface of necrotic, apoptotic, and ischaemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Therefore, the deposition and localisation of these pro-inflammatory isoforms of CRP have been demonstrated to amplify inflammation and tissue damage in a broad range of clinical conditions including ischaemia/reperfusion injury, Alzheimer's disease, age-related macular degeneration and immune thrombocytopaenia. Given the potentially broad relevance of CRP to disease pathology, the development of inhibitors of CRP remains an area of active investigation, which may pave the way for novel therapeutics for a diverse range of inflammatory diseases.
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Affiliation(s)
- James D McFadyen
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
- Department of Medicine, Monash University, Melbourne, VIC, Australia.
- Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
| | - Johannes Zeller
- Department of Plastic and Hand Surgery, Medical Faculty of the University of Freiburg, University of Freiburg Medical Centre, Freiburg, Germany
| | | | - Geoffrey A Pietersz
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Department of Immunology, Monash University, Melbourne, VIC, Australia
- Burnet Institute, Melbourne, VIC, Australia
| | - Steffen U Eisenhardt
- Department of Plastic and Hand Surgery, Medical Faculty of the University of Freiburg, University of Freiburg Medical Centre, Freiburg, Germany
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
- Department of Medicine, Monash University, Melbourne, VIC, Australia.
- Department of Immunology, Monash University, Melbourne, VIC, Australia.
- Heart Centre, The Alfred Hospital, Melbourne, VIC, Australia.
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35
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Ariza A, Torres MJ, Moreno-Aguilar C, Fernández-Santamaría R, Fernández TD. Early Biomarkers for Severe Drug Hypersensitivity Reactions. Curr Pharm Des 2019; 25:3829-3839. [DOI: 10.2174/1381612825666191107105440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023]
Abstract
Drug hypersensitivity reactions (DHRs) are typically classified into immediate and delayed reactions
based on the time interval between drug exposure and onset of symptoms. Clinical manifestations range from
mild to severe and life-threatening reactions. The most severe clinical entities are anaphylaxis and anaphylactic
shock for immediate reactions, and severe cutaneous adverse reactions such as Steven Johnson Syndrome and
Toxic Epidermal Necrolysis for delayed reactions. The diagnosis is complex and challenging, as drug provocation
tests and even skin tests can be very risky procedures, which makes them not recommended. Therefore, it is necessary
to search for useful early biomarkers to manage the diagnosis of these reactions. These biomarkers could
be useful to determine the clinical entity, but not to identify the culprit drug. Some of the currently available
biomarkers are few genetic associations of drug allergy with polymorphisms of human leukocyte antigen (HLA),
the detection of inflammatory and lipid mediators in serum, or the detection of cytokines, chemokines, and cytotoxic
markers in skin biopsies. In this literature review, it has been summarize the immunological mechanisms
involved in severe reactions, both immediate and delayed, and different early biomarkers: those currently used for
the diagnosis of these reactions as well as possible early biomarkers that could be useful with further studies to
standardize their clinical use.
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Affiliation(s)
- Adriana Ariza
- Allergy Research Group, Instituto de Investigacion Biomedica de Malaga-IBIMA, Malaga, Spain
| | - Maria J. Torres
- Allergy Research Group, Instituto de Investigacion Biomedica de Malaga-IBIMA, Malaga, Spain
| | - Carmen Moreno-Aguilar
- Immunology and Allergy Unit, IMIBICHospital Universitario Reina Sofía, Córdoba, Spain
| | | | - Tahia D. Fernández
- Allergy Research Group, Instituto de Investigacion Biomedica de Malaga-IBIMA, Malaga, Spain
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Lipecz A, Miller L, Kovacs I, Czakó C, Csipo T, Baffi J, Csiszar A, Tarantini S, Ungvari Z, Yabluchanskiy A, Conley S. Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions. GeroScience 2019; 41:813-845. [PMID: 31797238 PMCID: PMC6925092 DOI: 10.1007/s11357-019-00138-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 11/12/2019] [Indexed: 12/13/2022] Open
Abstract
Aging of the microcirculatory network plays a central role in the pathogenesis of a wide range of age-related diseases, from heart failure to Alzheimer's disease. In the eye, changes in the choroid and choroidal microcirculation (choriocapillaris) also occur with age, and these changes can play a critical role in the pathogenesis of age-related macular degeneration (AMD). In order to develop novel treatments for amelioration of choriocapillaris aging and prevention of AMD, it is essential to understand the cellular and functional changes that occur in the choroid and choriocapillaris during aging. In this review, recent advances in in vivo analysis of choroidal structure and function in AMD patients and patients at risk for AMD are discussed. The pathophysiological roles of fundamental cellular and molecular mechanisms of aging including oxidative stress, mitochondrial dysfunction, and impaired resistance to molecular stressors in the choriocapillaris are also considered in terms of their contribution to the pathogenesis of AMD. The pathogenic roles of cardiovascular risk factors that exacerbate microvascular aging processes, such as smoking, hypertension, and obesity as they relate to AMD and choroid and choriocapillaris changes in patients with these cardiovascular risk factors, are also discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay AMD by targeting fundamental cellular and molecular aging processes are presented.
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Affiliation(s)
- Agnes Lipecz
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Ophthalmology, Josa Andras Hospital, Nyiregyhaza, Hungary
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Lauren Miller
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd. BMSB553, Oklahoma City, OK, 73104, USA
| | - Illes Kovacs
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
- Department of Ophthalmology, Weill Cornell Medical College, New York City, NY, USA
| | - Cecília Czakó
- Department of Ophthalmology, Semmelweis University, Budapest, Hungary
| | - Tamas Csipo
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Judit Baffi
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Anna Csiszar
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Stefano Tarantini
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Zoltan Ungvari
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary
- International Training Program in Geroscience, Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Andriy Yabluchanskiy
- Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Shannon Conley
- Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd. BMSB553, Oklahoma City, OK, 73104, USA.
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Ruan CC, Gao PJ. Role of Complement-Related Inflammation and Vascular Dysfunction in Hypertension. Hypertension 2019; 73:965-971. [PMID: 30929519 DOI: 10.1161/hypertensionaha.118.11210] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Cheng-Chao Ruan
- From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
| | - Ping-Jin Gao
- From the State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension at Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, China
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Single-cell transcriptomics of the human retinal pigment epithelium and choroid in health and macular degeneration. Proc Natl Acad Sci U S A 2019; 116:24100-24107. [PMID: 31712411 PMCID: PMC6883845 DOI: 10.1073/pnas.1914143116] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The retinal pigment epithelium and the choroid are complex tissues whose dysfunction can lead to irreversible visual loss. In this study, single-cell RNA sequencing of both of these tissues was performed to characterize gene expression patterns specific to the retinal pigment epithelium and all major choroidal cell populations. Unique gene expression signatures of arterial, venous, and choriocapillaris vascular beds within the choroid were identified. RGCC, a gene that responds to complement and has been shown to induce endothelial apoptosis, was specifically expressed in choriocapillaris endothelial cells. This study provides potential insight into the molecular mechanisms of choroidal vascular disease and its contribution to age-related macular degeneration. The human retinal pigment epithelium (RPE) and choroid are complex tissues that provide crucial support to the retina. Disease affecting either of these supportive tissues can lead to irreversible blindness in the setting of age-related macular degeneration. In this study, single-cell RNA sequencing was performed on macular and peripheral regions of RPE-choroid from 7 human donor eyes in 2 independent experiments. In the first experiment, total RPE/choroid preparations were evaluated and expression profiles specific to RPE and major choroidal cell populations were identified. As choroidal endothelial cells represent a minority of the total RPE/choroidal cell population but are strongly implicated in age-related macular degeneration (AMD) pathogenesis, a second single-cell RNA-sequencing experiment was performed using endothelial cells enriched by magnetic separation. In this second study, we identified gene expression signatures along the choroidal vascular tree, classifying the transcriptome of human choriocapillaris, arterial, and venous endothelial cells. We found that the choriocapillaris highly and specifically expresses the regulator of cell cycle gene (RGCC), a gene that responds to complement activation and induces apoptosis in endothelial cells. In addition, RGCC was the most up-regulated choriocapillaris gene in a donor diagnosed with AMD. These results provide a characterization of the human RPE and choriocapillaris transcriptome, offering potential insight into the mechanisms of choriocapillaris response to complement injury and choroidal vascular disease in age-related macular degeneration.
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Label-Free Proteomics Revealed Oxidative Stress and Inflammation as Factors That Enhance Chemoresistance in Luminal Breast Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5357649. [PMID: 31485295 PMCID: PMC6702830 DOI: 10.1155/2019/5357649] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/22/2019] [Accepted: 07/01/2019] [Indexed: 12/29/2022]
Abstract
Breast cancer is the leading cause of cancer-associated death among women worldwide. Its high mortality rate is related to resistance towards chemotherapies, which is one of the major challenges of breast cancer research. In this study, we used label-free mass spectrometry- (MS-) based proteomics to investigate the differences between circulating proteins in the plasma of patients with chemoresponsive and chemoresistant luminal A breast cancer. MS analysis revealed 205 differentially expressed proteins. Furthermore, we used in silico tools to build protein-protein interaction networks. Most of the upregulated proteins in the chemoresistant group were closely related and tightly linked. The predominant networks were related to oxidative stress, the inflammatory response, and the complement cascade. Through this analysis, we identified inflammation and oxidative stress as central processes of breast cancer chemoresistance. Furthermore, we confirmed our hypothesis by evaluating oxidative stress and performing cytokine profiling in our cohort. The connections among oxidative stress, inflammation, and the complement system described in our study seem to indicate a pivotal axis in breast cancer chemoresistance. Hence, these findings will have significant clinical implications for improving therapies to bypass breast cancer chemoresistance in the future.
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40
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Rudolf M, Curcio CA, Schlötzer-Schrehardt U, Sefat AMM, Tura A, Aherrahrou Z, Brinkmann M, Grisanti S, Miura Y, Ranjbar M. Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates. ACTA ACUST UNITED AC 2019; 60:461-472. [DOI: 10.1167/iovs.18-25786] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Martin Rudolf
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
- Translational AMD Research Group Lübeck, University of Lübeck, Lübeck, Germany
| | - Christine A. Curcio
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States
| | | | - Armin Mir Mohi Sefat
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
- Translational AMD Research Group Lübeck, University of Lübeck, Lübeck, Germany
| | - Aysegül Tura
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
- German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany
- University Heart Centre Lübeck, Lübeck, Germany
| | - Max Brinkmann
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
- Laboratory for Angiogenesis & Ocular Cell Transplantation, University of Lübeck, Lübeck, Germany
| | | | - Yoko Miura
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
- Translational AMD Research Group Lübeck, University of Lübeck, Lübeck, Germany
- Institute of Biomedical Optics, University of Lübeck, Lübeck, Germany
| | - Mahdy Ranjbar
- Department of Ophthalmology, University of Lübeck, Lübeck, Germany
- Laboratory for Angiogenesis & Ocular Cell Transplantation, University of Lübeck, Lübeck, Germany
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41
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Yanagi Y, Foo VHX, Yoshida A. Asian age-related macular degeneration: from basic science research perspective. Eye (Lond) 2019; 33:34-49. [PMID: 30315261 PMCID: PMC6328602 DOI: 10.1038/s41433-018-0225-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/07/2018] [Accepted: 08/08/2018] [Indexed: 01/14/2023] Open
Abstract
In Asian populations, polypoidal choroidal vasculopathy (PCV), a distinct phenotype of neovascular age-related macular degeneration (AMD), is more prevalent than Caucasians. Recently, there has been significant focus on how PCV differs from typical AMD. Although typical AMD and PCV share a variety of mechanisms by which abnormal angiogenic process occurs at the retinochoroidal interface, PCV has different clinical characteristics such as aneurysm-like dilation at the terminal of choroidal neovascular membranes, less frequent drusen and inner choroidal degeneration due to the thickened choroid. Recent studies support an important role for inflammation, angiogenesis molecules and lipid metabolism in the pathogenesis of neovascular AMD. Furthermore, although less attention has been paid to the role of the choroid in AMD, accumulating evidence suggests that the choriocapillaris and choroid also play a pivotal role in drusenogenesis, typical AMD and PCV. This review discusses the basic pathogenic mechanisms of AMD and explores the difference between typical AMD and PCV.
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Affiliation(s)
- Yasuo Yanagi
- Singapore National Eye Centre, Singapore, Singapore.
- Singapore Eye Research Institute, Singapore, Singapore.
- Duke-NUS Medical School, Singapore, Singapore.
| | - Valencia Hui Xian Foo
- Singapore National Eye Centre, Singapore, Singapore
- Singapore Eye Research Institute, Singapore, Singapore
| | - Akitoshi Yoshida
- Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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42
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Toomey CB, Landowski M, Klingeborn M, Kelly U, Deans J, Dong H, Harrabi O, Van Blarcom T, Yeung YA, Grishanin R, Lin JC, Saban DR, Bowes Rickman C. Effect of Anti-C5a Therapy in a Murine Model of Early/Intermediate Dry Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2018; 59:662-673. [PMID: 29392311 PMCID: PMC5795897 DOI: 10.1167/iovs.17-23134] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Purpose A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of “dry” AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. Methods Heterozygous complement factor H (Cfh+/−) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/−∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. Results Aged Cfh+/− mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid–RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. Conclusions These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/−∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving “early” and “intermediate” AMD pathologies.
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Affiliation(s)
- Christopher B Toomey
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.,Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States.,Shiley Eye Institute, Department of Ophthalmology, University of California-San Diego, San Diego, California, United States
| | - Michael Landowski
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
| | - Mikael Klingeborn
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
| | - Una Kelly
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
| | - John Deans
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
| | - Holly Dong
- Rinat, Pfizer Inc, South San Francisco, California, United States
| | - Ons Harrabi
- Rinat, Pfizer Inc, South San Francisco, California, United States
| | | | - Yik Andy Yeung
- Rinat, Pfizer Inc, South San Francisco, California, United States
| | - Ruslan Grishanin
- Rinat, Pfizer Inc, South San Francisco, California, United States
| | - John C Lin
- Rinat, Pfizer Inc, South San Francisco, California, United States
| | - Daniel R Saban
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.,Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States
| | - Catherine Bowes Rickman
- Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.,Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, United States
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Baltu F, Sarici AM, Yildirim O, Mergen B, Bolat E. Investigation of vascular endothelial dysfunction in the patients with age-related macular degeneration. Cutan Ocul Toxicol 2018; 38:29-35. [PMID: 30037291 DOI: 10.1080/15569527.2018.1504056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
PURPOSE This study aims to evaluate the association between age-related macular degeneration (AMD) and cardiovascular disease by using the noninvasive flow-mediated dilation (FMD) test to show endothelial dysfunction as an indicator of subclinical atherosclerosis. METHOD Participants in this study included 30 dry AMD patients, 30 wet AMD patients, and 30 healthy controls without any systemic disease, including AMD. FMD and the intima media thickness (IMT) of the carotid artery were compared between the groups. RESULTS Comparison of FMD between the groups showed a 10.96% brachial artery dilation in the healthy controls, 3.99% in the dry AMD group, and 5.03% in the wet AMD group. While a significant difference was not observed between the wet and dry AMD groups, comparison of the control group to the wet and dry AMD groups yielded a significant difference. When brachial artery dilation below 7% was accepted as an abnormal FMD, 26.7% of the healthy controls, 66.7% of the dry AMD patients and 76.7% of the wet AMD patients were found to be abnormal. Similarly, while no significant difference was observed between the wet and dry AMD groups, comparison of the control group with the wet and dry AMD patients yielded a significant difference. When an IMT below 0.7 mm was accepted as abnormal, 26.7% of the healthy controls, 33.3% of the dry AMD, and 43.3% of the wet AMD were found to have an abnormal IMT. However, differences between the groups did not reach statistical significance. CONCLUSIONS In this study, use of the FMD test showed endothelial dysfunction among AMD patients. No significant differences were found between the dry and wet AMD patient groups.
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Affiliation(s)
- Fatih Baltu
- a Cerrahpasa Medical Faculty, Department of Ophthalmology , Istanbul University , Istanbul , Turkey
| | - Ahmet Murat Sarici
- a Cerrahpasa Medical Faculty, Department of Ophthalmology , Istanbul University , Istanbul , Turkey
| | - Onur Yildirim
- b Cerrahpasa Medical Faculty, Department of Radiology , Istanbul University , Istanbul , Turkey
| | - Burak Mergen
- a Cerrahpasa Medical Faculty, Department of Ophthalmology , Istanbul University , Istanbul , Turkey
| | - Erkut Bolat
- c Cerrahpasa Medical Faculty, Department of Biostatistics and Medical Informatics , Istanbul University , Istanbul , Turkey
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McFadyen JD, Kiefer J, Braig D, Loseff-Silver J, Potempa LA, Eisenhardt SU, Peter K. Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes. Front Immunol 2018; 9:1351. [PMID: 29946323 PMCID: PMC6005900 DOI: 10.3389/fimmu.2018.01351] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/31/2018] [Indexed: 11/26/2022] Open
Abstract
C-reactive protein (CRP) is a member of the pentraxin superfamily that is widely recognized as a marker of inflammatory reactions and cardiovascular risk in humans. Recently, a growing body of data is emerging, which demonstrates that CRP is not only a marker of inflammation but also acts as a direct mediator of inflammatory reactions and the innate immune response. Here, we critically review the various lines of evidence supporting the concept of a pro-inflammatory “CRP system.” The CRP system consists of a functionally inert circulating pentameric form (pCRP), which is transformed to its highly pro-inflammatory structural isoforms, pCRP* and ultimately to monomeric CRP (mCRP). While retaining an overall pentameric structure, pCRP* is structurally more relaxed than pCRP, thus exposing neoepitopes important for immune activation and complement fixation. Thereby, pCRP* shares its pro-inflammatory properties with the fully dissociated structural isoform mCRP. The dissociation of pCRP into its pro-inflammatory structural isoforms and thus activation of the CRP system occur on necrotic, apoptotic, and ischemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Both pCRP* and mCRP can cause activation of platelets, leukocytes, endothelial cells, and complement. The localization and deposition of these pro-inflammatory structural isoforms of CRP in inflamed tissue appear to be important mediators for a range of clinical conditions, including ischemia/reperfusion (I/R) injury of various organs, cardiovascular disease, transplant rejection, Alzheimer’s disease, and age-related macular degeneration. These findings provide the impetus to tackle the vexing problem of innate immunity response by targeting CRP. Understanding the “activation process” of CRP will also likely allow the development of novel anti-inflammatory drugs, thereby providing potential new immunomodulatory therapeutics in a broad range of inflammatory diseases.
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Affiliation(s)
- James D McFadyen
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.,Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Jurij Kiefer
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - David Braig
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Julia Loseff-Silver
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Lawrence A Potempa
- College of Pharmacy, Roosevelt University, Schaumburg, IL, United States
| | - Steffen Ulrich Eisenhardt
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Heart Centre, The Alfred Hospital, Melbourne, VIC, Australia.,Department of Immunology, Monash University, Melbourne, VIC, Australia
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45
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Molins B, Romero-Vázquez S, Fuentes-Prior P, Adan A, Dick AD. C-Reactive Protein as a Therapeutic Target in Age-Related Macular Degeneration. Front Immunol 2018; 9:808. [PMID: 29725335 PMCID: PMC5916960 DOI: 10.3389/fimmu.2018.00808] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 04/03/2018] [Indexed: 01/26/2023] Open
Abstract
Age-related macular degeneration (AMD), a retinal degenerative disease, is the leading cause of central vision loss among the elderly population in developed countries and an increasing global burden. The major risk is aging, compounded by other environmental factors and association with genetic variants for risk of progression. Although the etiology of AMD is not yet clearly understood, several pathogenic pathways have been proposed, including dysfunction of the retinal pigment epithelium, inflammation, and oxidative stress. The identification of AMD susceptibility genes encoding complement factors and the presence of complement and other inflammatory mediators in drusen, the hallmark deposits of AMD, support the concept that local inflammation and immune-mediated processes play a key role in AMD pathogenesis that may be accelerated through systemic immune activation. In this regard, increased levels of circulating C-reactive protein (CRP) have been associated with higher risk of AMD. Besides being a risk marker for AMD, CRP may also play a role in the progression of the disease as it has been identified in drusen, and we have recently found that its monomeric form (mCRP) induces blood retinal barrier disruption in vitro. In this review, we will address recent evidence that links CRP and AMD pathogenesis, which may open new therapeutic opportunities to prevent the progression of AMD.
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Affiliation(s)
- Blanca Molins
- Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sara Romero-Vázquez
- Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Pablo Fuentes-Prior
- Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.,Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Alfredo Adan
- Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Barcelona, Spain
| | - Andrew D Dick
- Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.,Academic Unit of Ophthalmology, School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.,National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital, University College London Institute of Ophthalmology, London, United Kingdom
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46
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Jo DH, Kim JH, Yang W, Kim H, Chang S, Kim D, Chang M, Lee K, Chung J, Kim JH. Anti-complement component 5 antibody targeting MG4 domain inhibits choroidal neovascularization. Oncotarget 2018; 8:45506-45516. [PMID: 28477014 PMCID: PMC5542204 DOI: 10.18632/oncotarget.17221] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 03/15/2017] [Indexed: 12/27/2022] Open
Abstract
Age-related macular degeneration (AMD) is one of the main causes of visual impairment in adults. Visual deterioration is more prominent in neovascular AMD with choroidal neovascularization (CNV). Clinical and postmortem studies suggested that complement system activation might induce CNV. In this study, we demonstrated that an anti-mouse complement component 5 (C5) antibody targeting MG4 domain of β chain effectively inhibited CNV which was induced by laser photocoagulation in mice. The targeted epitope of this anti-C5 antibody was different from that of currently utilized anti-C5 antibody (eculizumab) in the MG7 domain in which a single nucleotide polymorphism (R885H/C) results in poor response to eculizumab. Even with targeting MG4 domain, this anti-C5 antibody reduced production of C5a, monocyte chemoattractant protein-1 and vascular endothelial growth factor to prevent infiltration of F4/80-positive cells into CNV lesions and formation of CNV. Furthermore, anti-C5 antibody targeting MG4 domain induced no definite toxicity in normal retina. These results demonstrated that anti-C5 antibody targeting MG4 domain inhibited CNV in neovascular AMD.
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Affiliation(s)
- Dong Hyun Jo
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences and Protein Metabolism, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Hyoung Kim
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Wonjun Yang
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Cancer Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyori Kim
- Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Shinjae Chang
- Biotechnology Research Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Dongjo Kim
- Biotechnology Research Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Minseok Chang
- Biotechnology Research Institute, Celltrion, Inc., Incheon, Republic of Korea
| | - Kihwang Lee
- Department of Ophthalmology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Junho Chung
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Cancer Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Hun Kim
- Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Biomedical Sciences and Protein Metabolism, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
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Chirco KR, Potempa LA. C-Reactive Protein As a Mediator of Complement Activation and Inflammatory Signaling in Age-Related Macular Degeneration. Front Immunol 2018; 9:539. [PMID: 29599782 PMCID: PMC5862805 DOI: 10.3389/fimmu.2018.00539] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 03/02/2018] [Indexed: 12/13/2022] Open
Abstract
Age-related macular degeneration (AMD) is a devastating neurodegenerative disease affecting millions worldwide. Complement activation, inflammation, and the loss of choroidal endothelial cells have been established as key factors in both normal aging and AMD; however, the exact mechanisms for these events have yet to be fully uncovered. Herein, we provide evidence that the prototypic acute phase reactant, C-reactive protein (CRP), contributes to AMD pathogenesis. We discuss serum CRP levels as a risk factor for disease, immunolocalization of distinct forms of CRP in the at-risk and diseased retina, and direct effects of CRP on ocular tissue. Furthermore, we discuss the complement system as it relates to AMD pathophysiology, provide a model for the role of CRP in this disease, and outline current therapies being developed and tested to treat AMD patients.
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48
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Mohlin C, Sandholm K, Kvanta A, Ekdahl KN, Johansson K. A model to study complement involvement in experimental retinal degeneration. Ups J Med Sci 2018; 123:28-42. [PMID: 29436895 PMCID: PMC5901466 DOI: 10.1080/03009734.2018.1431744] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The complement system (CS) plays a role in the pathogenesis of a number of ocular diseases, including diabetic retinopathy (DR), glaucoma, uveitis, and age-related macular degeneration (AMD). Given that many of the complex eye-related degenerative diseases have limited treatment opportunities, we aimed to mimic the in vivo retinal degenerative process by developing a relevant co-culture system. METHOD AND MATERIALS The adult porcine retina was co-cultured with the spontaneously arising human retinal pigment epithelial cells-19 (ARPE-19). RESULTS Inflammatory activity was found after culture and included migrating microglial cells, gliosis, cell death, and CS activation (demonstrated by a minor increase in the secreted anaphylotoxin C3a in co-culture). CS components, including C1q, C3, C4, soluble C5b-9, and the C5a receptor, were expressed in the retina and/or ARPE cells after culture. C1q, C3, and CS regulators such as C4 binding protein (C4BP), factor H (CFH), and factor I (CFI) were secreted after culture. DISCUSSION Thus, our research indicates that this co-culturing system may be useful for investigations of the CS and its involvement in experimental neurodegenerative diseases.
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Affiliation(s)
- Camilla Mohlin
- Linnaeus University Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
- CONTACT Camilla Mohlin Linnaeus Center of Biomaterials Chemistry, Linnaeus University, 391 82 Kalmar, Sweden
| | - Kerstin Sandholm
- Linnaeus University Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
| | - Anders Kvanta
- Department of Clinical Neuroscience, Section for Ophthalmology and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Kristina N. Ekdahl
- Linnaeus University Faculty of Health and Life Science, Linnaeus Center of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden
| | - Kjell Johansson
- School of Medical Sciences, Örebro University, Örebro, Sweden
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49
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Natarajan N, Abbas Y, Bryant DM, Gonzalez-Rosa JM, Sharpe M, Uygur A, Cocco-Delgado LH, Ho NN, Gerard NP, Gerard CJ, MacRae CA, Burns CE, Burns CG, Whited JL, Lee RT. Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration. Circulation 2018; 137:2152-2165. [PMID: 29348261 PMCID: PMC5953786 DOI: 10.1161/circulationaha.117.030801] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration. METHODS Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control. RESULTS Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1. CONCLUSIONS These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.
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Affiliation(s)
- Niranjana Natarajan
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.)
| | - Yamen Abbas
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.)
| | - Donald M Bryant
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.).,Department of Orthopedic Surgery, Brigham & Women's Hospital, Cambridge, MA (D.M.B., J.L.W.).,Allen Discovery Center, Tufts University, Medford, MA (D.M.B., J.L.W.)
| | - Juan Manuel Gonzalez-Rosa
- Harvard Medical School and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.M.G.-R., M.S., C.E.B., C.G.B.)
| | - Michka Sharpe
- Harvard Medical School and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.M.G.-R., M.S., C.E.B., C.G.B.)
| | - Aysu Uygur
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.)
| | - Lucas H Cocco-Delgado
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.)
| | - Nhi Ngoc Ho
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.)
| | - Norma P Gerard
- Division of Respiratory Diseases, Boston Children's Hospital, MA (C.J.G., N.P.G.).,Department of Medicine, Harvard Medical School, Boston, MA (C.J.G., N.P.G.).,Beth Israel Deaconess Medical Center, Boston, MA (C.J.G., N.P.G.)
| | - Craig J Gerard
- Division of Respiratory Diseases, Boston Children's Hospital, MA (C.J.G., N.P.G.).,Department of Medicine, Harvard Medical School, Boston, MA (C.J.G., N.P.G.).,Beth Israel Deaconess Medical Center, Boston, MA (C.J.G., N.P.G.)
| | - Calum A MacRae
- Department of Medicine, Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (C.A.M., R.T.L.)
| | - Caroline E Burns
- Harvard Medical School and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.M.G.-R., M.S., C.E.B., C.G.B.)
| | - C Geoffrey Burns
- Harvard Medical School and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (J.M.G.-R., M.S., C.E.B., C.G.B.)
| | - Jessica L Whited
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.).,Department of Orthopedic Surgery, Brigham & Women's Hospital, Cambridge, MA (D.M.B., J.L.W.).,Allen Discovery Center, Tufts University, Medford, MA (D.M.B., J.L.W.)
| | - Richard T Lee
- Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA (N.N., Y.A., D.M.B., A.U., L.H.C.-D., N.N.H., J.L.W., R.T.L.) .,Department of Medicine, Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (C.A.M., R.T.L.)
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Anaphylatoxin Signaling in Retinal Pigment and Choroidal Endothelial Cells: Characteristics and Relevance to Age-Related Macular Degeneration. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1074:45-51. [PMID: 29721926 DOI: 10.1007/978-3-319-75402-4_6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness in the USA. Polymorphisms in various complement components are associated with an increased risk for AMD, and it has been hypothesized that an overactive complement system is partially responsible for the pathology of AMD. AMD is classified as early, intermediate, or late AMD, depending on the degree of the associated pathologies. Late AMD can be characterized as either lesions associated with neovascular AMD or geographic atrophy. Both sets of lesions are associated with pathology at the RPE/choroid interface, which include a thickening of Bruch's membrane, presence of drusen, and pigmentary alterations, and deterioration of the blood-retina barrier has been reported. These changes can lead to the slow degeneration and atrophy of the photoreceptors in the macula in dry AMD, or progress to choroidal neovascularization (CNV) and leakage of these new vessels in wet AMD. It has been shown previously that complement anaphylatoxins C3a and C5a, signaling via their respective G-protein-coupled receptors, can alter RPE cell function and promote choroidal neovascularization. However, it is important to note these components also play a role in tissue repair. Here we discuss anaphylatoxin signaling in AMD-related target cells and the potential implications for the design of anti-complement therapeutics.
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