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Wei Y, Lv Z, Du Z, Xiao T. The structural characteristics and expression characteristics of C1S in response to GCRV infection in grass carp. FISH & SHELLFISH IMMUNOLOGY 2025; 161:110264. [PMID: 40058677 DOI: 10.1016/j.fsi.2025.110264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/14/2025] [Accepted: 03/06/2025] [Indexed: 03/15/2025]
Abstract
The complement system, a critical component of innate immunity in fish, plays a pivotal role in the defense against Grass Carp Reovirus (GCRV) infection in grass carp. This study explores the structural characteristics of C1S, a crucial molecule in the classical pathway of the complement system, and its involvement in the response to GCRV infection. We found that the grass carp C1S gene comprises six domains similar to those in mammals: two CUB (Complement C1r/C1s, Uegf, Bmp1) domains, two CCP (Complement control protein) domains, one EGFCA (Calcium-binding epidermal growth factor) domain, and one Tryp_SPc (Trypsin-like serine protease) domain, albeit without chromosomal collinearity to humans. Comparative analysis revealed that the identity and similarity of this gene with those in other species range from 30.6 to 89.4 % and 30.7-89.7 %, respectively. Phylogenetic analysis positioned C1S in close relation with R. klamathensis and D. rerio. Tissue expression profiles in both healthy and GCRV-infected grass carp indicated primary expression of C1S in the liver, with expression peaks at day 7 post-infection in the liver and spleen, and at day 5 in the kidney. Functional assays demonstrated that C1S activates the complement system via cleavage of complement component 3 (C3) into C3b, further inhibiting GCRV replication and upregulating antiviral genes IFN1, IRF3, and IRF7. These findings elucidate the mechanism by which the complement system mediates resistance to GCRV infection in grass carp, offering a substantial theoretical foundation for further research.
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Affiliation(s)
- Yuling Wei
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China; College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China
| | - Zhao Lv
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Zongjun Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Tiaoyi Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China.
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2
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Cui CS, Lerskiatiphanich T, Li XX, Giri R, Liu N, Kumar V, Whittaker AK, Han FY, Clark RJ, Begun J, Lee JD, Woodruff TM. Colon-targeted complement C5a 1 receptor inhibition using pH-sensitive nanoparticles ameliorates experimental colitis. Br J Pharmacol 2025. [PMID: 40288760 DOI: 10.1111/bph.70056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 03/11/2025] [Accepted: 03/19/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND AND PURPOSE The complement system is associated with inflammatory bowel disease (IBD) pathology. Complement activation induces C5a production, which signals through the C5a1 receptor (C5aR1) to drive inflammatory responses that may underlie IBD. EXPERIMENTAL APPROACH We examined mucosal biopsies from ulcerative colitis patients and identified C5a1 receptor up-regulated in active lesions, supporting the C5a1 receptor as a target for therapeutic intervention. Cyclic peptide C5a1 receptor antagonists such as PMX205 are orally efficacious in preclinical colitis models; however, their clinical application may be limited by rapid metabolism. We therefore encapsulated PMX205 within pH-sensitive polymers to target drug for colon delivery following oral administration. KEY RESULTS PMX205 nanoparticles were non-toxic and released bioactive PMX205 in simulated colon fluid. In vivo imaging of Cy5-labelled nanoparticles demonstrated rapid entry and persistence in the mouse colon for up to 48 h. Next, we utilised the dextran sodium sulphate-induced colitis model to examine efficacy of the C5a1 receptor-antagonist formulation. We show that oral administration of PMX205 nanoparticles every 2 days from symptom onset significantly mitigated weight loss, clinical illness, colon length reduction and epithelial damage to a similar degree as C5a1 receptor-/- mice. Notably, unformulated PMX205 was markedly less effective in this dosing regimen. CONCLUSION AND IMPLICATIONS This novel colon-targeted formulation therefore offers a potent therapeutic strategy for translating C5a1 receptor antagonists for IBD conditions such as ulcerative colitis.
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Affiliation(s)
- Cedric S Cui
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Titaya Lerskiatiphanich
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Xaria X Li
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Rabina Giri
- Mater Research Institute, Translational Research Institute, Brisbane, Queensland, Australia
| | - Ning Liu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Vinod Kumar
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew K Whittaker
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Queensland, Australia
| | - Felicity Y Han
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Queensland, Australia
| | - Richard J Clark
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Jakob Begun
- Mater Research Institute, Translational Research Institute, Brisbane, Queensland, Australia
| | - John D Lee
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
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Feng X, Zhang L, Jiao K, Li Y, Wu M, Xie Y, Xiao L. Tracking astrocyte polarization in the retina in retinopathy of prematurity. Exp Eye Res 2025; 250:110170. [PMID: 39577607 DOI: 10.1016/j.exer.2024.110170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/08/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Astrocyte patterns affect the normal development of the retinal vascular network in retinopathy of prematurity (ROP), which is associated with VEGF secretion. However, the role of the astrocyte polarization in this process remains unknown. Therefore, this study aimed to track the status of A1/A2 reactive astrocytes in the retinas of the oxygen-induced retinopathy (OIR) model and their association with VEGF expression. The C57BL/6 mouse OIR model was constructed to characterize the pathological changes in ROP. Immunofluorescence of iB4 and GFAP staining was performed to observe changes in the vascular network and astrocyte pattern at different time points (P0, P7, P12, P17, and P21). C3-labeled A1 reactive and S100A10-labeled A2 reactive astrocytes and VEGF were also observed. The pattern of GFAP-labeled astrocyte was altered concurrently with the iB4-positive vascular network during OIR. Astrocyte activity was significantly weakened at P12 and significantly enhanced at P17. Notably, the number of C3-labeled A1 reactive astrocytes was significantly increased at P12, decreased at P17, and normalized at P21 in OIR models. S100A10-labeled A2 reactive astrocytes were significantly increased at P17 but did not change significantly at P12 or P17. VEGF levels were decreased at P7-P12 and increased at P12-P17. The expression pattern of VEGF was opposite to that of C3-labeled A1 reactive astrocytes and identical to that of S100A10-labeled A2 reactive astrocytes. In conclusion, the astrocyte pattern and vascular network exhibited similar changes during the OIR process, and the periods of vaso-obliteration and neo-vascularization display an abnormal activation in A1-and A2-reactive astrocytes.
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Affiliation(s)
- Xiaoxiao Feng
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Liwei Zhang
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Kangwei Jiao
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Yunqing Li
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Min Wu
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Yu Xie
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China
| | - Libo Xiao
- Department of Ophthalmology, Affiliated Hospital of Yunnan University, The Second People's Hospital of Yunnan Province, No.176, Qingnian Road, Kunming, Yunnan, 650000, China.
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Liu H, Yuan Y, Johnson-Stephenson TK, Jing C, Zhang M, Huang J, Zen K, Li L, Zhu D. Signal regulatory protein α dynamically mediates macrophage polarization facilitated alleviation of ischemic diseases. Cell Biosci 2024; 14:150. [PMID: 39707436 DOI: 10.1186/s13578-024-01325-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 11/14/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND macrophage-targeting therapy of ischemic disease has made progress in clinic trial. However, the role and underlying mechanism of pro-inflammatory or anti-inflammatory polarized macrophages in modulating ischemic diseases remain incompletely understood. RESULTS here we examine the effect of pro-inflammatory (LPS) and anti-inflammatory (IL-4) macrophage on ischemic diseases in a mouse ischemic hindlimb and heart model, and identify that signal regulatory protein α (Sirpα) modulates macrophage polarization induced angiogenesis via promoting phagocytosis or activating HIF1α nucleus relocation in macrophages, respectively. More importantly, the therapeutic effect of polarized macrophages is controlled by Sirpα in a time-dependent manner. Downregulation of macrophage Sirpα at the early-stage or upregulation of macrophage Sirpα at the late-stage of ischemic disease enhances the therapeutic effect. In contrast, increasing Sirpα at the early-stage or decreasing it at the late-stage leads to failure of inducing ischemic disease resilience. Mechanistically, we find that signal transducer and activator of transcription 3 and 6 (Stat3 and Stat6) mediate downregulation (pro-inflammatory polarization) or upregulation (anti-inflammatory polarization) of Sirpα, respectively. CONCLUSION Our results reveal that dynamic regulation of macrophage by Sirpα plays a critical role in alleviating ischemic diseases.
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Affiliation(s)
- Haiyi Liu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yonghui Yuan
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | | | - Chenyang Jing
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Mingchao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China
| | - Jun Huang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ke Zen
- State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University School of Life Sciences, Nanjing, Jiangsu, China.
| | - Limin Li
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Dihan Zhu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China.
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Liu G, He X, Zhao G, Lu Z. Complement regulation in tumor immune evasion. Semin Immunol 2024; 76:101912. [PMID: 39579520 DOI: 10.1016/j.smim.2024.101912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/18/2024] [Accepted: 11/18/2024] [Indexed: 11/25/2024]
Abstract
The complement system plays crucial roles in both innate and adaptive immune responses, facilitating the elimination of pathogens such as microorganisms and damaged cells, including cancer cells. It is tightly regulated and integrated with cell-mediated immunity. In the tumor microenvironment, the complement system performs both immune and nonimmune functions in tumor and immune cells through pathways that depend on or are independent of complement activation, thereby promoting immune evasion and tumor progression.
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Affiliation(s)
- Guijun Liu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Xuxiao He
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China
| | - Gaoxiang Zhao
- Department of Oncology, Cancer Institute of The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266061, China
| | - Zhimin Lu
- Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China; Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China; Zhejiang University Cancer Center, Hangzhou, Zhejiang 310029, China.
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Pugh D, Patel D, Macnaught G, Czopek A, Bruce L, Donachie J, Gallacher PJ, Tan S, Ahlman M, Grayson PC, Basu N, Dhaun N. 18F-FDG-PET/MR imaging to monitor disease activity in large vessel vasculitis. Nat Commun 2024; 15:7314. [PMID: 39183340 PMCID: PMC11345444 DOI: 10.1038/s41467-024-51613-1] [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: 11/23/2023] [Accepted: 08/14/2024] [Indexed: 08/27/2024] Open
Abstract
Disease-monitoring in large vessel vasculitis (LVV) is challenging. Simultaneous 18F-fluorodeoxyglucose positron emission tomography with magnetic resonance imaging (PET/MRI) provides functional assessment of vascular inflammation alongside high-definition structural imaging with a relatively low burden of radiation exposure. Here, we investigate the ability of PET/MRI to monitor LVV disease activity longitudinally in a prospective cohort of patients with active LVV. We demonstrate that both the PET and MRI components of the scan can distinguish active from inactive disease using established quantification methods. Using logistic-regression modelling of PET/MRI metrics, we devise a novel PET/MRI-specific Vasculitis Activity using MR PET (VAMP) score which is able to distinguish active from inactive disease with more accuracy than established methods and detects changes in disease activity longitudinally. These findings are evaluated in an independent validation cohort. Finally, PET/MRI improves clinicians' assessment of LVV disease activity and confidence in disease management, as assessed via clinician survey. In summary, PET/MRI may be useful in tracking disease activity and assessing treatment-response in LVV. Based on our findings, larger, prospective studies assessing PET/MRI in LVV are now warranted.
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Affiliation(s)
- Dan Pugh
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Dilip Patel
- Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | | | - Alicja Czopek
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Lorraine Bruce
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - James Donachie
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Peter J Gallacher
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Sovira Tan
- National Institute of Arthritis & Musculoskeletal & Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark Ahlman
- Department of Radiology & Imaging, Medical College of Georgia, Georgia, USA
| | - Peter C Grayson
- National Institute of Arthritis & Musculoskeletal & Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Neil Basu
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK
| | - Neeraj Dhaun
- BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
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7
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Wei Y, Lv Z, Xiao T, Du Z. The role of MASP1 in the complement system and expression characteristics in response to GCRV infection in grass carp. FISH & SHELLFISH IMMUNOLOGY 2024; 151:109712. [PMID: 38901682 DOI: 10.1016/j.fsi.2024.109712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/17/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
The grass carp (Ctenopharyngodon idella) constitutes a significant economic resource within the aquaculture sector of our nation, yet it has been chronically afflicted by the Grass Carp Reovirus (GCRV) disease. The complement system, a vital component of fish's innate immunity, plays a crucial role in combating viral infections. This research investigates the potential role of MASP1, a key molecule in the lectin pathway of the complement system, in the GCRV infection in grass carp. An analysis of the molecular characteristics of MASP1 in grass carp revealed that its identity and similarity percentages range from 35.10 to 91.00 % and 35.30-91.00 %, respectively, in comparison to other species. Phylogenetically, MASP1 in C. idella aligns closely with species such as Danio rerio, Cyprinus carpio, and Carassius carassius, exhibiting chromosomal collinearity with the zebrafish. Subsequent tissue analysis in both healthy and GCRV-infected grass carp indicated that MASP1's basal expression was predominantly in the liver. Post-GCRV infection, MASP1 expression in various tissues exhibited temporal variations: peaking in the liver on day 5, spleen on day 7, and kidney on day 14. Furthermore, employing Complement Component 3 (C3) as a benchmark for complement system activation, it was observed that MASP1 could activate and cleave C3 to C3b. MASP1 also demonstrated an inhibitory effect on GCRV replication (compared with the control group, VP2 and VP7 decreased by 6.82-fold and 4.37-fold) and enhanced the expression of antiviral genes, namely IRF3, IRF7 and IFN1 (compared with the control group, increased 2.25-fold, 45.38-fold and 22.37-fold, respectively). In vivo protein injection experiments substantiated MASP1's influence on the relative mRNA expression levels of C3 in various tissues and its protein expression in serum. This study also verified that C3 could modulate the expression of antiviral genes such as IFN1 and IRF3.
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Affiliation(s)
- Yuling Wei
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Zhao Lv
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Tiaoyi Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan, 410128, China.
| | - Zongjun Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
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Ong J, Zarnegar A, Selvam A, Driban M, Chhablani J. The Complement System as a Therapeutic Target in Retinal Disease. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:945. [PMID: 38929562 PMCID: PMC11205777 DOI: 10.3390/medicina60060945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/16/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024]
Abstract
The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.
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Affiliation(s)
- Joshua Ong
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI 48105, USA
| | - Arman Zarnegar
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Amrish Selvam
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Matthew Driban
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Jay Chhablani
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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Wilke GA, Apte RS. Complement regulation in the eye: implications for age-related macular degeneration. J Clin Invest 2024; 134:e178296. [PMID: 38690727 PMCID: PMC11060743 DOI: 10.1172/jci178296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024] Open
Abstract
Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.
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Affiliation(s)
- Georgia A. Wilke
- John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences
| | - Rajendra S. Apte
- John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences
- Department of Medicine, and
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA
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10
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Azubuike-Osu SO, Kuhs A, Götz P, Faro A, Preissner KT, Arnholdt C, Deindl E. Treatment with Cobra Venom Factor Decreases Ischemic Tissue Damage in Mice. Biomedicines 2024; 12:309. [PMID: 38397911 PMCID: PMC10886846 DOI: 10.3390/biomedicines12020309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/23/2024] [Accepted: 01/27/2024] [Indexed: 02/25/2024] Open
Abstract
Tissue ischemia, caused by the blockage of blood vessels, can result in substantial damage and impaired tissue performance. Information regarding the functional contribution of the complement system in the context of ischemia and angiogenesis is lacking. To investigate the influence of complement activation and depletion upon femoral artery ligation (FAL), Cobra venom factor (CVF) (that functionally resembles C3b, the activated form of complement component C3) was applied in mice in comparison to control mice. Seven days after induction of muscle ischemia through FAL, gastrocnemius muscles of mice were excised and subjected to (immuno-)histological analyses. H&E and apoptotic cell staining (TUNEL) staining revealed a significant reduction in ischemic tissue damage in CVF-treated mice compared to controls. The control mice, however, exhibited a significantly higher capillary-to-muscle fiber ratio and a higher number of proliferating endothelial cells (CD31+/CD45-/BrdU+). The total number of leukocytes (CD45+) substantially decreased in CVF-treated mice versus control mice. Moreover, the CVF-treated group displayed a shift towards the M2-like anti-inflammatory and regenerative macrophage phenotype (CD68+/MRC1+). In conclusion, our findings suggest that treatment with CVF leads to reduced ischemic tissue damage along with decreased leukocyte recruitment but increased numbers of M2-like polarized macrophages, thereby enhancing tissue regeneration, repair, and healing.
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Affiliation(s)
- Sharon O. Azubuike-Osu
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Alex Ekwueme Federal University Ndufu Alike, Abakaliki 482131, Ebonyi, Nigeria
| | - Amelie Kuhs
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Anna Faro
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Klaus T. Preissner
- Department of Cardiology, Kerckhoff-Heart Research Institute, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany;
| | - Christoph Arnholdt
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany or (S.O.A.-O.); (A.K.); (P.G.); (A.F.); (C.A.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
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11
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Nording H, Baron L, Sauter M, Lübken A, Rawish E, Szepanowski R, von Esebeck J, Sun Y, Emami H, Meusel M, Saraei R, Schanze N, Gorantla SP, von Bubnoff N, Geisler T, von Hundelshausen P, Stellos K, Marquardt J, Sadik CD, Köhl J, Duerschmied D, Kleinschnitz C, Langer HF. Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor-modulating factors. Blood Adv 2023; 7:6411-6427. [PMID: 37257194 PMCID: PMC10598500 DOI: 10.1182/bloodadvances.2021006891] [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: 12/22/2021] [Revised: 02/16/2023] [Accepted: 02/26/2023] [Indexed: 06/02/2023] Open
Abstract
In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1-/- mice but not in C5-/- mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1-/-CXCL4-/- mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
| | - Antje Lübken
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Elias Rawish
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Rebecca Szepanowski
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Jacob von Esebeck
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Ying Sun
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Hossein Emami
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Moritz Meusel
- University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Roza Saraei
- University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Nancy Schanze
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sivahari Prasad Gorantla
- Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany
| | - Nikolas von Bubnoff
- Department of Hematology and Oncology, Medical Center, University of Schleswig-Holstein, Lübeck, Germany
| | - Tobias Geisler
- Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tuebingen, Germany
| | - Philipp von Hundelshausen
- Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Konstantinos Stellos
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Department of Cardiovascular Research, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jens Marquardt
- First Department of Medicine, University of Schleswig-Holstein, Lübeck, Germany
| | | | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Schleswig-Holstein, Lübeck, Germany
| | - Daniel Duerschmied
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Kleinschnitz
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
- Cardioimmunology Group, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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12
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Wei Y, Lv Z, Liu Q, Yu J, Xiao Y, Du Z, Xiao T. Structural comparison and expression function analysis of BF/C2 in Ctenopharyngodon idella and Squaliobarbus curriculus. FISH & SHELLFISH IMMUNOLOGY 2023; 142:109154. [PMID: 37821003 DOI: 10.1016/j.fsi.2023.109154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/17/2023] [Accepted: 10/08/2023] [Indexed: 10/13/2023]
Abstract
Ctenopharyngodon idella and Squaliobarbus curriculus, members of the Cyprinidae family and Yaroideae subfamily, have shown different levels of resistance to grass carp reo virus (GCRV), with S. curriculus exhibiting higher resilience. In the pursuit to explore the distinctions in the structural and expression traits of BF/C2 (A,B) between the two species, we conducted an analysis involving the cloning and examination of various coding sequences (CDS). We successfully cloned the CDS of ci-BF/C2A and ci-BF/C2B from C. idella, which spanned 2259 bp and 2514 bp respectively, encoding 752 and 837 amino acids. Similarly, the CDS of sc-BF/C2A and sc-BF/C2B from S. curriculus were cloned, featuring lengths of 1353 bp and 2517 bp and encoding 450 and 838 amino acids, respectively. A chromosome collinearity assessment revealed that ci-BF/C2A demonstrated collinearity with sc-BF/C2A, a finding not replicated with ci-BF/C2B and sc-BF/C2B. Delving into gene structure, we discerned that ci-BF/C2A harbored a greater number of Tryp_SPc domains compared to sc-BF/C2A. Following this, we engineered and purified six prokaryotic recombinant proteins: CI-BF/C2A, CI-BF/C2A1 (a variant resulting from the deletion of the Tryp_SPc domain of CI-BF/C2A), CI-BF/C2A2 (representing the Tryp_SPc domain of CI-BF/C2A), CI-BF/C2B, SC-BF/C2A, and SC-BF/C2B. Through serum co-incubation tests with these recombinant proteins, we established the activation of the complement marker C3 in each case. Utilizing fluorescence quantitative expression analysis, we observed ubiquitous expression of ci-BF/C2A and ci-BF/C2B across all grass carp tissues, predominantly in the liver. This pattern mirrored in S. curriculus, where sc-BF/C2A was highly expressed in the gills, and sc-BF/C2B manifested notably in the liver. Kidney cell infection experiments on both species revealed enhanced resistance to GCRV post-incubation with the recombinant proteins. Notably, cells treated with SC-BF/C2 (A, B) exhibited pronounced resilience compared to those treated with CI-BF/C2 (A, B, A1, A2). However, cells incubated with CI-BF/C2A1 and CI-BF/C2A2 showed strengthen resistance relative to cells treated with CI-BF/C2A and CI-BF/C2B. In GCRV infection trials on grass carp, ci-BF/C2A and ci-BF/C2B expressions reached a zenith on the seventh day post-infection, highlighting a distinctive functional mode in immune defense against GCRV infection orchestrated by BF/C2. The empirical data underscores the pivotal role of the Tryp_SPc domain in immune responses to GCRV infection, pinpointing its influence on ci-BF/C2A expression. Conclusively, this investigation provides a foundational understanding of the unique immune function characteristics of BF/C2 in grass carp, paving the way for further scholarly exploration in this realm.
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Affiliation(s)
- Yuling Wei
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China; Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Zhao Lv
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Qiaolin Liu
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Jianbo Yu
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Yu Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China
| | - Zongjun Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.
| | - Tiaoyi Xiao
- Hunan Engineering Technology Research Center of Featured Aquatic Resources Utilization, Hunan Agricultural University, Changsha, Hunan 410128, China.
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13
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Khanani AM, Patel SS, Staurenghi G, Tadayoni R, Danzig CJ, Eichenbaum DA, Hsu J, Wykoff CC, Heier JS, Lally DR, Monés J, Nielsen JS, Sheth VS, Kaiser PK, Clark J, Zhu L, Patel H, Tang J, Desai D, Jaffe GJ. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet 2023; 402:1449-1458. [PMID: 37696275 DOI: 10.1016/s0140-6736(23)01583-0] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/25/2023] [Accepted: 07/28/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth. METHODS GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 μL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366. FINDINGS Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group. INTERPRETATION Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy. FUNDING Iveric Bio, An Astellas Company.
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Affiliation(s)
- Arshad M Khanani
- Sierra Eye Associates, Reno, NV, USA; University of Nevada, Reno School of Medicine, Reno, NV, USA.
| | | | - Giovanni Staurenghi
- Eye Clinic, Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
| | - Ramin Tadayoni
- Université Paris Cité, Ophthalmology Department, AP-HP, Lariboisière, Saint Louis and Fondation Adolphe de Rothschild Hospitals, Paris, France
| | - Carl J Danzig
- Rand Eye Institute, Deerfield Beach, FL, USA; Florida Atlantic University, Charles E Schmidt School of Medicine, Boca Raton, FL, USA
| | - David A Eichenbaum
- Retina Vitreous Associates of Florida, Saint Petersburg, FL, USA; Morsani College of Medicine at the University of South Florida, Tampa, FL, USA
| | - Jason Hsu
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA, USA
| | - Charles C Wykoff
- Retina Consultants of Texas, Retina Consultants of America, Houston, TX, USA; Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA
| | | | - David R Lally
- New England Retina Consultants, Springfield, MA, USA
| | - Jordi Monés
- Institut de la Màcula, Centro Médico Teknon, Barcelona, Spain
| | | | | | - Peter K Kaiser
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Julie Clark
- Iveric Bio, An Astellas Company, Parsippany, NJ, USA
| | - Liansheng Zhu
- Iveric Bio, An Astellas Company, Parsippany, NJ, USA
| | - Hersh Patel
- Iveric Bio, An Astellas Company, Parsippany, NJ, USA
| | - Justin Tang
- Iveric Bio, An Astellas Company, Parsippany, NJ, USA
| | - Dhaval Desai
- Iveric Bio, An Astellas Company, Parsippany, NJ, USA
| | - Glenn J Jaffe
- Department of Ophthalmology, Duke University, Durham, NC, USA
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14
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Nording H, Baron L, Lübken A, Emami H, von Esebeck J, Meusel M, Sadik C, Schanze N, Duerschmied D, Köhl J, Münch G, Langer HF. The Platelet Anaphylatoxin Receptor C5aR1 (CD88) Is a Promising Target for Modulating Vessel Growth in Response to Ischemia a. TH OPEN 2023; 7:e289-e293. [PMID: 37868192 PMCID: PMC10586890 DOI: 10.1055/a-2156-8048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023] Open
Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Antje Lübken
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Hossein Emami
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Jacob von Esebeck
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Moritz Meusel
- Medical Clinic II, University Hospital, University Heart Center Lübeck, Lübeck, Germany
| | - Christian Sadik
- Clinic for Dermatology, University of Lübeck, University Hospital, Lübeck, Germany
| | - Nancy Schanze
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Daniel Duerschmied
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
- European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jörg Köhl
- ISEF, University of Lübeck, Lübeck, Germany
| | | | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
- Clinic for Dermatology, University of Lübeck, University Hospital, Lübeck, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Germany
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15
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Khan A, Hussain S, Iyer JK, Kaul A, Bonnewitz M, Kaul R. Human papillomavirus-mediated expression of complement regulatory proteins in human cervical cancer cells. Eur J Obstet Gynecol Reprod Biol 2023; 288:222-228. [PMID: 37572452 DOI: 10.1016/j.ejogrb.2023.07.014] [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: 05/17/2023] [Revised: 07/18/2023] [Accepted: 07/24/2023] [Indexed: 08/14/2023]
Abstract
OBJECTIVES This study aimed to evaluate the expression pattern of complement regulatory proteins (CRPs) CD46, CD59, and CD55 in HPV-positive (HPV+) & negative (HPV-) cervical cancer cell lines in search of a reliable differential biomarker. STUDY DESIGN We analysed the expression of CRPs in HPV 16-positive SiHa cell line, HPV 18-positive HeLa cell line, and HPV-negative cell line C33a using RT-qPCR, Western blotting, flow cytometry, and confocal microscopy. RESULTS We observed a differential expression profile of CRPs in HPV+ and HPV- cervical cancer cell lines. The mRNA level of CD59 & CD55 showed a higher expression pattern in HPV+ cells when compared to HPV- cancer cells. However, flow cytometry-based experiments revealed that CD46 was preferentially expressed more in HPV 16-positive SiHa cells followed by HPV 18-positive HeLa cells when compared to HPV- C33a cells. Interestingly, confocal microscopy revealed a high level of CD59 expression in Hela cells and SiHa cells but low expression in HPV- C33a cells. In addition, HPV 18-positive HeLa cells expressed more CD55, which was lower in SiHa cells and very weak in C33a cells. CONCLUSION The study demonstrates the differential expression of CRPs in both HPV+ and HPV- cervical cancer cells for the first time, and their potential to serve as an early diagnostic marker for cervical carcinogenesis.
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Affiliation(s)
- Asiya Khan
- Dr. Babasaheb R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India; Amity Institute of Biotechnology, Amity University, Noida 201303, India
| | - Showket Hussain
- Division of Molecular Oncology & Molecular Diagnostics, Indian Council of Medical Research-National Institute of Cancer Prevention and Research, Noida 201301, India
| | - Janaki K Iyer
- Department of Biochemistry and Microbiology, Oklahoma State University Centre for Health Sciences, 1111 West 17(th) Street, Tulsa, OK 74107, USA; Department of Natural Sciences, Northeastern State University, Broken Arrow, OK 74014, USA
| | - Anil Kaul
- Health Care Administration, Oklahoma State University Centre for Health Sciences, Tulsa, OK 74107, USA
| | - Mackenzie Bonnewitz
- Department of Natural Sciences, Northeastern State University, Broken Arrow, OK 74014, USA
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University Centre for Health Sciences, 1111 West 17(th) Street, Tulsa, OK 74107, USA.
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Hanna J, Ah-Pine F, Boina C, Bedoui Y, Gasque P, Septembre-Malaterre A. Deciphering the Role of the Anaphylatoxin C3a: A Key Function in Modulating the Tumor Microenvironment. Cancers (Basel) 2023; 15:cancers15112986. [PMID: 37296948 DOI: 10.3390/cancers15112986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
The complement system plays a crucial role in cancer development. Our study investigated the role of C3a anaphylatoxin on the tumor microenvironment. Our models consisted of mesenchymal stem cells (MSC-like, 3T3-L1), macrophages (Raw 264.7 Blue, (RB)) and tumor cells (melanoma B16/F0). Recombinant mouse (Mo) C3a (rC3a) was produced in CHO cells transfected with a Mo-IL10-signal peptide-Mo C3a plasmid construct. The effects of rC3a, IFN-γ, TGF-β1, and LPS were tested on the expression of C3, C3aR, PI3K, cytokines, chemokines, transcription factors, antioxidant defense mechanisms, angiogenesis and macrophage polarization (M1/M2). 3T3-L1 expressed the highest levels of C3, while C3aR was expressed more by RB. Interestingly, expression of C3/3T3-L1 and C3aR/RB was markedly upregulated by IFN-γ. rC3a was found to upregulate the expression of anti-inflammatory cytokines (IL-10) on 3T3-L1 and TGF-β1 on RB. rC3a also upregulated the expression of pro-inflammatory cytokines in RB. The expression of CCL-5 increased in 3T3-L1 in response to rC3a. On RB, rC3a did not alter M1/M2 polarization but upregulated the expression of antioxidant defense genes, HO-1, and VEGF. C3/C3a produced mainly by MSC may play a critical role in TME remodeling by stimulating both anti-inflammatory and proangiogenic activities of tumor stromal cells.
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Affiliation(s)
- Jolimar Hanna
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Laboratoire d'Immunologie Clinique et Expérimentale OI (LICE OI), CHU de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
| | - Franck Ah-Pine
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Service d'Anatomie et Cytologie Pathologiques, CHU de La Réunion, Avenue François Mitterrand BP450, 97448 Saint-Pierre, France
| | - Chailas Boina
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Laboratoire d'Immunologie Clinique et Expérimentale OI (LICE OI), CHU de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
| | - Yosra Bedoui
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Service d'Anatomie et Cytologie Pathologiques, CHU de La Réunion, Avenue François Mitterrand BP450, 97448 Saint-Pierre, France
| | - Philippe Gasque
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Laboratoire d'Immunologie Clinique et Expérimentale OI (LICE OI), CHU de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
| | - Axelle Septembre-Malaterre
- Unité de Recherche EPI (Études Pharmaco-Immunologiques), Université de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
- Laboratoire d'Immunologie Clinique et Expérimentale OI (LICE OI), CHU de La Réunion, Allée des Topazes, 97405 Saint-Denis, France
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17
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Triggianese P, Conigliaro P, De Martino E, Monosi B, Chimenti MS. Overview on the Link Between the Complement System and Auto-Immune Articular and Pulmonary Disease. Open Access Rheumatol 2023; 15:65-79. [PMID: 37214353 PMCID: PMC10198272 DOI: 10.2147/oarrr.s318826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/05/2023] [Indexed: 05/24/2023] Open
Abstract
Complement system (CS) dysregulation is a key factor in the pathogenesis of different autoimmune diseases playing a central role in many immune innate and adaptive processes. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by ta breach of self-tolerance leading to a synovitis and extra-articular manifestations. The CS is activated in RA and seems not only to mediate direct tissue damage but also play a role in the initiation of RA pathogenetic mechanisms through interactions with citrullinated proteins. Interstitial lung disease (ILD) represents the most common extra-articular manifestation that can lead to progressive fibrosis. In this review, we focused on the evidence of CS dysregulation in RA and in ILD, and highlighted the role of the CS in both the innate and adaptive immune responses in the development of diseases, by using idiopathic pulmonary fibrosis as a model of lung disease. As a proof of concept, we dissected the evidence that several treatments used to treat RA and ILD such as glucocorticoids, pirfenidone, disease modifying antirheumatic drugs, targeted biologics such as tumor necrosis factor (TNF)-inhibitors, rituximab, tocilizumab, and nintedanib may act indirectly on the CS, suggesting that the CS might represent a potential therapeutic target in these complex diseases.
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Affiliation(s)
- Paola Triggianese
- Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
| | - Paola Conigliaro
- Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
| | - Erica De Martino
- Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
| | - Benedetta Monosi
- Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
| | - Maria Sole Chimenti
- Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, Italy
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18
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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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19
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Azzarito G, Henry M, Rotshteyn T, Leeners B, Dubey RK. Transcriptomic and Functional Evidence That miRNA193a-3p Inhibits Lymphatic Endothelial Cell (LEC) and LEC + MCF-7 Spheroid Growth Directly and by Altering MCF-7 Secretome. Cells 2023; 12:cells12030389. [PMID: 36766731 PMCID: PMC9913637 DOI: 10.3390/cells12030389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/12/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
MicroRNA 193a-3p (miR193a-3p) is a short non-coding RNA with tumor suppressor properties. Breast cancer (BC) progression is governed by active interaction between breast cancer cells, vascular (V)/lymphatic (L) endothelial cells (ECs), and BC secretome. We have recently shown that miR193a-3p, a tumor suppressor miRNA, inhibits MCF-7 BC cell-driven growth of VECs via direct antimitogenic actions and alters MCF-7 secretome. Since LEC-BC cross-talk plays a key role in BC progression, we investigated the effects of miR193a-3p on MCF-7 secretome and estradiol-mediated growth effects in LECs and LEC + MCF-7 spheroids, and delineated the underlying mechanisms. Transfection of LECs with miR193a-3p, as well as secretome from MCF-7 transfected cells, inhibited LEC growth, and these effects were mimicked in LEC + MCF-7 spheroids. Moreover, miR193a-3p inhibited ERK1/2 and Akt phosphorylation in LECs and LEC + MCF-7 spheroids, which are importantly involved in promoting cancer development and metastasis. Treatment of LECs and LEC + MCF-7 spheroids with estradiol (E2)-induced growth, as well as ERK1/2 and Akt phosphorylation, and was abrogated by miR193a-3p and secretome from MCF-7 transfected cells. Gene expression analysis (GEA) in LEC + MCF-7 spheroids transfected with miR193a-3p showed significant upregulation of 54 genes and downregulation of 73 genes. Pathway enrichment analysis of regulated genes showed significant modulation of several pathways, including interferon, interleukin/cytokine-mediated signaling, innate immune system, ERK1/2 cascade, apoptosis, and estrogen receptor signaling. Transcriptomic analysis showed downregulation in interferon and anti-apoptotic and pro-growth molecules, such as IFI6, IFIT1, OSA1/2, IFITM1, HLA-A/B, PSMB8/9, and PARP9, which are known to regulate BC progression. The cytokine proteome array of miR193a-3p transfected MCF secretome and confirmed the upregulation of several growth inhibitory cytokines, including IFNγ, Il-1a, IL-1ra, IL-32, IL-33, IL-24, IL-27, cystatin, C-reactive protein, Fas ligand, MIG, and sTIM3. Moreover, miR193a-3p alters factors in MCF-7 secretome, which represses ERK1/2 and Akt phosphorylation, induces pro-apoptotic protein and apoptosis in LECs, and downregulates interferon-associated proteins known to promote cancer growth and metastasis. In conclusion, miR193a-3p can potentially modify the tumor microenvironment by altering pro-growth BC secretome and inhibiting LEC growth, and may represent a therapeutic molecule to target breast tumors/cancer.
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Affiliation(s)
- Giovanna Azzarito
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland
| | - Margit Henry
- Center for Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Tamara Rotshteyn
- Center for Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Brigitte Leeners
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland
| | - Raghvendra K. Dubey
- Department of Reproductive Endocrinology, University Hospital Zurich, 8952 Schlieren, Switzerland
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Correspondence:
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20
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Zarantonello A, Revel M, Grunenwald A, Roumenina LT. C3-dependent effector functions of complement. Immunol Rev 2023; 313:120-138. [PMID: 36271889 PMCID: PMC10092904 DOI: 10.1111/imr.13147] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce the C3 forms (native C3, C3 [H2 O], and intracellular C3), the C3 fragments C3a, C3b, iC3b, and C3dg/C3d, and the C3 expression sites. To highlight the important role that C3 plays in human biological processes, we will give an overview of the diseases linked to C3 deficiency and to uncontrolled C3 activation. Next, we will present a structural description of C3 activation and of the C3 fragments generated by complement regulation. We will proceed by describing the C3a interaction with the anaphylatoxin receptor, followed by the interactions of opsonins (C3b, iC3b, and C3dg/C3d) with complement receptors, divided into two groups: receptors bearing complement regulatory functions and the effector receptors without complement regulatory activity. We outline the molecular architecture of the receptors, their binding sites on the C3 activation fragments, the cells expressing them, the diversity of their functions, and recent advances. With this review, we aim to give an up-to-date analysis of the processes triggered by C3 activation fragments on different cell types in health and disease contexts.
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Affiliation(s)
- Alessandra Zarantonello
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Margot Revel
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Anne Grunenwald
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
| | - Lubka T Roumenina
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
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21
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Janneh AH, Kassir MF, Atilgan FC, Lee HG, Sheridan M, Oleinik N, Szulc Z, Voelkel-Johnson C, Nguyen H, Li H, Peterson YK, Marangoni E, Saatci O, Sahin O, Lilly M, Atkinson C, Tomlinson S, Mehrotra S, Ogretmen B. Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis. Cell Rep 2022; 41:111742. [PMID: 36476873 PMCID: PMC9791981 DOI: 10.1016/j.celrep.2022.111742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 08/15/2022] [Accepted: 11/07/2022] [Indexed: 12/12/2022] Open
Abstract
Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'2 is associated with PPIL1 through glutamic acid 156 (E156) and aspartic acid 111 (D111) residues, resulting in NLRP3/inflammasome induction. Inactivation mutations of S1PR1 to prevent S1P signaling or mutations of C3b-α'2 to prevent its association with PPIL1 attenuate inflammasome activation and reduce lung colonization/metastasis in mice. Also, activation of the S1PR1/C3/PPIL1/NLRP3 axis is highly associated with human metastatic melanoma tissues and patient-derived xenografts. Moreover, targeting S1PR1/C3/PPIL1/NLRP3 signaling using molecular, genetic, and pharmacologic tools prevents lung colonization/metastasis of various murine cancer cell lines using WT and C3a-receptor1 knockout (C3aR1-/-) mice. These data provide strategies for treating high-grade/metastatic tumors by targeting the S1PR1/C3/inflammasome axis.
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Affiliation(s)
- Alhaji H Janneh
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Mohamed Faisal Kassir
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - F Cansu Atilgan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Han Gyul Lee
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Megan Sheridan
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Natalia Oleinik
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Zdzislaw Szulc
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Christina Voelkel-Johnson
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Hung Nguyen
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Hong Li
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Public Health, College of Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Yuri K Peterson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | | | - Ozge Saatci
- Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Ozgur Sahin
- Department of Drug Discovery and Biomedical Sciences, School of Pharmacy, University of South Carolina, Columbia, SC 29208, USA
| | - Michael Lilly
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Carl Atkinson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Stephen Tomlinson
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
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22
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Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice. Cell Death Dis 2022; 13:975. [PMID: 36402750 PMCID: PMC9675822 DOI: 10.1038/s41419-022-05416-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/03/2022] [Accepted: 11/07/2022] [Indexed: 11/21/2022]
Abstract
Muscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.
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23
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Yednock T, Fong DS, Lad EM. C1q and the classical complement cascade in geographic atrophy secondary to age-related macular degeneration. Int J Retina Vitreous 2022; 8:79. [PMID: 36348407 PMCID: PMC9641935 DOI: 10.1186/s40942-022-00431-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 10/21/2022] [Indexed: 11/10/2022] Open
Abstract
Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a retinal neurodegenerative disorder. Human genetic data support the complement system as a key component of pathogenesis in AMD, which has been further supported by pre-clinical and recent clinical studies. However, the involvement of the different complement pathways (classical, lectin, alternative), and thus the optimal complement inhibition target, has yet to be fully defined. There is evidence that C1q, the initiating molecule of the classical pathway, is a key driver of complement activity in AMD. C1q is expressed locally by infiltrating phagocytic cells and C1q-activating ligands are present at disease onset and continue to accumulate with disease progression. The accumulation of C1q on photoreceptor synapses with age and disease is consistent with its role in synapse elimination and neurodegeneration that has been observed in other neurodegenerative disorders. Furthermore, genetic deletion of C1q, local pharmacologic inhibition within the eye, or genetic deletion of downstream C4 prevents photoreceptor cell damage in mouse models. Hence, targeting the classical pathway in GA could provide a more specific therapeutic approach with potential for favorable efficacy and safety.
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Affiliation(s)
- Ted Yednock
- Annexon Biosciences, 1400 Sierra Point Parkway Building C, 2nd Floor, Brisbane, CA, 94005, USA
| | - Donald S Fong
- Annexon Biosciences, 1400 Sierra Point Parkway Building C, 2nd Floor, Brisbane, CA, 94005, USA.
| | - Eleonora M Lad
- Department of Ophthalmology, Duke University Medical Center, 2351 Erwin Rd, Durham, NC, 27705, USA
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24
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Götz P, Azubuike-Osu SO, Braumandl A, Arnholdt C, Kübler M, Richter L, Lasch M, Bobrowski L, Preissner KT, Deindl E. Cobra Venom Factor Boosts Arteriogenesis in Mice. Int J Mol Sci 2022; 23:ijms23158454. [PMID: 35955584 PMCID: PMC9368946 DOI: 10.3390/ijms23158454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 01/27/2023] Open
Abstract
Arteriogenesis, the growth of natural bypass blood vessels, can compensate for the loss of arteries caused by vascular occlusive diseases. Accordingly, it is a major goal to identify the drugs promoting this innate immune system-driven process in patients aiming to save their tissues and life. Here, we studied the impact of the Cobra venom factor (CVF), which is a C3-like complement-activating protein that induces depletion of the complement in the circulation in a murine hind limb model of arteriogenesis. Arteriogenesis was induced in C57BL/6J mice by femoral artery ligation (FAL). The administration of a single dose of CVF (12.5 µg) 24 h prior to FAL significantly enhanced the perfusion recovery 7 days after FAL, as shown by Laser Doppler imaging. Immunofluorescence analyses demonstrated an elevated number of proliferating (BrdU+) vascular cells, along with an increased luminal diameter of the grown collateral vessels. Flow cytometric analyses of the blood samples isolated 3 h after FAL revealed an elevated number of neutrophils and platelet-neutrophil aggregates. Giemsa stains displayed augmented mast cell recruitment and activation in the perivascular space of the growing collaterals 8 h after FAL. Seven days after FAL, we found more CD68+/MRC-1+ M2-like polarized pro-arteriogenic macrophages around growing collaterals. These data indicate that a single dose of CVF boosts arteriogenesis by catalyzing the innate immune reactions, relevant for collateral vessel growth.
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Affiliation(s)
- Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Sharon O. Azubuike-Osu
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medicine, Alex Ekwueme Federal University Ndufu Alike, Abakaliki 482131, Ebonyi, Nigeria
| | - Anna Braumandl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Christoph Arnholdt
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Lisa Richter
- Flow Cytometry Core Facility, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany;
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Lisa Bobrowski
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Klaus T. Preissner
- Department of Cardiology, Kerckhoff-Heart Research Institute, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany;
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); or (S.O.A.-O.); (A.B.); (C.A.); (M.K.); (M.L.); (L.B.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Correspondence: ; Tel.: +49-(0)-89-2180-76504
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25
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Sodhi EU, Philpott HT, Carter MM, Birmingham TB, Appleton CT. Sex-Differences and Associations Between Complement Activation and Synovial Vascularization in Patients with Late-Stage Knee Osteoarthritis. Front Immunol 2022; 13:890094. [PMID: 35686134 PMCID: PMC9170895 DOI: 10.3389/fimmu.2022.890094] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Purpose Synovial inflammation in knee osteoarthritis (OA) causes disorganized synovial angiogenesis and complement activation in synovial fluid, but links between complement and synovial microvascular pathology have not been established. Since complement causes vascular pathology in other diseases and since sex-differences exist in complement activation and in OA, we investigated sex differences in synovial fluid complement factors, synovial tissue vascular pathology, and associations between complement and synovial vascular pathology in patients with late-stage knee OA. Methods Patients with symptomatic, late-stage radiographic knee OA undergoing total knee arthroplasty or high tibial osteotomy provided matched synovial fluid and tissue biopsies during surgery. Complement factors (C2, C5, adipsin, MBL, and CFI) and terminal complement complex (sC5b-C9) were measured in synovial fluid by multiplex or enzyme-linked immunosorbent assay, respectively. Features of synovial vascular pathology (vascularization, perivascular edema, and vasculopathy) were assessed by histopathology. Multivariate linear regression models were used to assess associations between synovial fluid complement factors and histopathological features of vascular pathology, with adjustment for age, sex, body mass index, and sex interaction. Sex-disaggregated comparisons were completed. Results Synovial fluid biomarker and histopathology data were included from 97 patients. Most synovial fluid complement factors and synovial tissue histopathological features were similar between sexes. Synovial fluid C5 trended to lower levels in males (-20.93 ng/mL [95%CI -42.08, 0.23] p=0.05). Median vasculopathy scores (0.42 [95%CI 0.07, 0.77] p=0.02) were higher in males. In the full cohort, C5 concentration was associated with lower vascularization scores (-0.005 [95%CI -0.010, -0.0001] p=0.04) while accounting for sex*C5 interaction. In sex-disaggregated analyses, increased C5 concentration was associated with lower vascularization scores (-0.005 [95%CI –0.009, -0.0001] p=0.04) in male patients, but not in female patients. Males had higher sC5b-C9 compared to females. Additionally, males with high C5 had a higher synovial fluid concentration of sC5b-C9 compared to males with low C5. No differences were found in females. Conclusion Higher synovial fluid C5 levels were associated with increased complement activation and decreased synovial vascularization in males but not in females with OA. Future studies should test whether synovial fluid complement activation suppresses synovial angiogenesis and identify mechanisms accounting for C5-related sex-differences in synovial fluid complement activation in patients with knee OA.
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Affiliation(s)
- Emily U Sodhi
- Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Holly T Philpott
- Health & Rehabilitation Sciences, Faculty of Health Sciences, Western University, London, ON, Canada.,Bone & Joint Institute, Western University, London, ON, Canada
| | - McKenzie M Carter
- Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Bone & Joint Institute, Western University, London, ON, Canada
| | - Trevor B Birmingham
- Health & Rehabilitation Sciences, Faculty of Health Sciences, Western University, London, ON, Canada.,Bone & Joint Institute, Western University, London, ON, Canada
| | - C Thomas Appleton
- Department of Physiology & Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.,Health & Rehabilitation Sciences, Faculty of Health Sciences, Western University, London, ON, Canada.,Bone & Joint Institute, Western University, London, ON, Canada.,Department of Medicine, Schulich School of Medicine, Western University, London, ON, Canada
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26
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Wang CW, Lee YC, Chang CC, Lin YJ, Liou YA, Hsu PC, Chang CC, Sai AKO, Wang CH, Chao TK. A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker. Cancers (Basel) 2022; 14:cancers14071651. [PMID: 35406422 PMCID: PMC8996991 DOI: 10.3390/cancers14071651] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer is a common malignant gynecological disease. Molecular target therapy, i.e., antiangiogenesis with bevacizumab, was found to be effective in some patients of epithelial ovarian cancer (EOC). Although careful patient selection is essential, there are currently no biomarkers available for routine therapeutic usage. To the authors’ best knowledge, this is the first automated precision oncology framework to effectively identify and select EOC and peritoneal serous papillary carcinoma (PSPC) patients with positive therapeutic effect. From March 2013 to January 2021, we have a database, containing four kinds of immunohistochemical tissue samples, including AIM2, c3, C5 and NLRP3, from patients diagnosed with EOC and PSPC and treated with bevacizumab in a hospital-based retrospective study. We developed a hybrid deep learning framework and weakly supervised deep learning models for each potential biomarker, and the experimental results show that the proposed model in combination with AIM2 achieves high accuracy 0.92, recall 0.97, F-measure 0.93 and AUC 0.97 for the first experiment (66% training and 34%testing) and high accuracy 0.86 ± 0.07, precision 0.9 ± 0.07, recall 0.85 ± 0.06, F-measure 0.87 ± 0.06 and AUC 0.91 ± 0.05 for the second experiment using five-fold cross validation, respectively. Both Kaplan-Meier PFS analysis and Cox proportional hazards model analysis further confirmed that the proposed AIM2-DL model is able to distinguish patients gaining positive therapeutic effects with low cancer recurrence from patients with disease progression after treatment (p < 0.005).
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan;
| | - Yu-Ching Lee
- Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei 106335, Taiwan;
| | - Cheng-Chang Chang
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei 11490, Taiwan; (C.-C.C.); (P.-C.H.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-Jia Lin
- Department of Pathology, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Yi-An Liou
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Po-Chao Hsu
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei 11490, Taiwan; (C.-C.C.); (P.-C.H.)
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan
| | - Chun-Chieh Chang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Aung-Kyaw-Oo Sai
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei 106335, Taiwan; (C.-W.W.); (Y.-A.L.); (C.-C.C.); (A.-K.-O.S.)
| | - Chih-Hung Wang
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Taipei 11490, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei 11490, Taiwan;
- Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence:
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27
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Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Am J Obstet Gynecol 2022; 226:S1059-S1070. [PMID: 32986992 DOI: 10.1016/j.ajog.2020.09.038] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/19/2020] [Accepted: 09/23/2020] [Indexed: 12/20/2022]
Abstract
The complement system is critical to human health owing to its central role in host defense and innate immunity. During pregnancy, the complement system must be appropriately regulated to allow for immunologic tolerance to the developing fetus and placenta. Although some degree of complement activation can be seen in normal pregnancy, the fetus seems to be protected in part through the placental expression of complement regulatory proteins, which inhibit complement activation at different steps along the complement activation cascade. In women who develop preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, there is a shift toward increased complement activation and decreased complement regulation. There is an increase in placental deposition of C5b-9, which is the terminal effector of classical, lectin, and alternative complement pathways. C5b-9 deposition stimulates trophoblasts to secrete soluble fms-like tyrosine kinase-1, which sequesters vascular endothelial growth factor and placental growth factor. Pathogenic mutations or deletions in complement regulatory genes, which predispose to increased complement activation, have been detected in women with preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Before the disease, biomarkers of alternative complement pathway activation are increased; during active disease, biomarkers of terminal complement pathway activation are increased. Urinary excretion of C5b-9 is associated with preeclampsia with severe features and distinguishes it from other hypertensive disorders of pregnancy. Taken together, existing data link preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome with increased activation of the terminal complement pathway that, in some cases, may be influenced by genetic alterations in complement regulators. These findings suggest that the inhibition of the terminal complement pathway, possibly through C5 blockade, may be an effective strategy to treat preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, but this strategy warrants further evaluation in clinical trials.
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28
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Abstract
Tumorigenesis has long been linked to the evasion of the immune system and the uncontrolled proliferation of transformed cells. The complement system, a major arm of innate immunity, is a key factor in the progression of cancer because many of its components have critical regulatory roles in the tumor microenvironment. For example, complement anaphylatoxins directly and indirectly inhibit antitumor T-cell responses in primary and metastatic sites, enhance proliferation of tumor cells, and promote metastasis and tumor angiogenesis. Many recent studies have provided evidence that cancer is able to hijack the immunoregulatory components of the complement system which fundamentally are tasked with protecting the body against abnormal cells and pathogens. Indeed, recent evidence shows that many types of cancer use C1q receptors (C1qRs) to promote tumor growth and progression. More importantly, most cancer cells express both C1q and its major receptors (gC1qR and cC1qR) on their surface which are essential for cell proliferation and survival. In this review, we discuss the ability of cancer to control and manipulate the complement system in the tumor microenvironment and identify possible therapeutic targets, including C1q and gC1qR.
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Affiliation(s)
- Danyaal Ain
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Talha Shaikh
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Samantha Manimala
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
| | - Berhane Ghebrehiwet
- The Department of Medicine, Stony Brook University, 100 Nicholls Road, Stony Brook, NY 11794-8161, USA
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29
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Abstract
The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3's functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3's relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.
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Affiliation(s)
- Benjamin J Kim
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Tianyu Liu
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | - John D Lambris
- Department of Laboratory Medicine and Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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30
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Functional Identification of Complement Factor D and Analysis of Its Expression during GCRV Infection in Grass Carp ( Ctenopharyngodon idella). Int J Mol Sci 2021; 22:ijms222112011. [PMID: 34769442 PMCID: PMC8584590 DOI: 10.3390/ijms222112011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/19/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
Complement factor D (Df) is a serine protease well known for activating the alternative pathway (AP) in mammals by promoting the cleavage of complement component 3 (C3), thus becoming involved in innate defense. In teleost fish, however, the functional mechanisms of Df in the AP and against pathogen infection are far from clear. In the present study, we cloned and characterized the Df gene, CiDf, from grass carp (Ctenopharyngodon idella) and analyzed its function in promoting C3 cleavage and expression changes after grass carp reovirus (GCRV) infection. The open reading frame of CiDf was found to be 753 bp, encoding 250 amino acids with a molecular mass of 27.06 kDa. CiDf harbors a conserved Tryp_SPc domain, with three conserved residues representing the catalytic triad and three conserved binding sites in the substrate specificity pocket. Pairwise alignment showed that CiDf shares the highest identity (96%) and similarity (98%) with Df from Anabarilius grahami. Phylogenetic analysis indicated that CiDf and other fish Dfs formed a distinct evolutionary branch. Similar to most Dfs from other vertebrates, the CiDf gene structure is characterized by four introns and five exons. The incubation of recombinant CiDf protein with grass carp serum significantly increased the C3b content, demonstrating the conserved function of CiDf in the AP in promoting C3 cleavage, similar to Dfs in mammals. CiDf mRNA expression was widely detected in various tissues and levels were relatively higher in the liver, spleen, and intestine of grass carp. During GCRV infection over a 168-hour period, a high level of CiDf mRNA expression in the liver, spleen, and intestine was maintained at 144 and 168 h, suggesting AP activity at the late stage of GCRV infection. Collectively, the above results reveal the conserved structure and function of CiDf and its distinct expression patterns after GCRV infection, which provide a key basis for studying the roles of Df and AP during GCRV infection in the grass carp C. idella.
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31
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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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32
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Iturriaga-Goyon E, Buentello-Volante B, Magaña-Guerrero FS, Garfias Y. Future Perspectives of Therapeutic, Diagnostic and Prognostic Aptamers in Eye Pathological Angiogenesis. Cells 2021; 10:cells10061455. [PMID: 34200613 PMCID: PMC8227682 DOI: 10.3390/cells10061455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/04/2021] [Accepted: 06/05/2021] [Indexed: 12/23/2022] Open
Abstract
Aptamers are single-stranded DNA or RNA oligonucleotides that are currently used in clinical trials due to their selectivity and specificity to bind small molecules such as proteins, peptides, viral particles, vitamins, metal ions and even whole cells. Aptamers are highly specific to their targets, they are smaller than antibodies and fragment antibodies, they can be easily conjugated to multiple surfaces and ions and controllable post-production modifications can be performed. Aptamers have been therapeutically used for age-related macular degeneration, cancer, thrombosis and inflammatory diseases. The aim of this review is to highlight the therapeutic, diagnostic and prognostic possibilities associated with aptamers, focusing on eye pathological angiogenesis.
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Affiliation(s)
- Emilio Iturriaga-Goyon
- MD/PhD (PECEM) Program, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
- Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, Mexico City 06800, Mexico; (B.B.-V.); (F.S.M.-G.)
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad 3000, Mexico City 04510, Mexico
| | - Beatriz Buentello-Volante
- Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, Mexico City 06800, Mexico; (B.B.-V.); (F.S.M.-G.)
| | - Fátima Sofía Magaña-Guerrero
- Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, Mexico City 06800, Mexico; (B.B.-V.); (F.S.M.-G.)
| | - Yonathan Garfias
- Cell and Tissue Biology, Research Unit, Institute of Ophthalmology, Conde de Valenciana, Chimalpopoca 14, Mexico City 06800, Mexico; (B.B.-V.); (F.S.M.-G.)
- Department of Biochemistry, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad 3000, Mexico City 04510, Mexico
- Correspondence:
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Nording H, Baron L, Haberthür D, Emschermann F, Mezger M, Sauter M, Sauter R, Patzelt J, Knoepp K, Nording A, Meusel M, Meyer-Saraei R, Hlushchuk R, Sedding D, Borst O, Eitel I, Karsten CM, Feil R, Pichler B, Erdmann J, Verschoor A, Chavakis E, Chavakis T, von Hundelshausen P, Köhl J, Gawaz M, Langer HF. The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nat Commun 2021; 12:3352. [PMID: 34099640 PMCID: PMC8185003 DOI: 10.1038/s41467-021-23499-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 03/28/2021] [Indexed: 02/05/2023] Open
Abstract
Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Lasse Baron
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - David Haberthür
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Frederic Emschermann
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Matthias Mezger
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Reinhard Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Johannes Patzelt
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Kai Knoepp
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Anne Nording
- grid.10392.390000 0001 2190 1447Institute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany
| | - Moritz Meusel
- grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Roza Meyer-Saraei
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Ruslan Hlushchuk
- grid.5734.50000 0001 0726 5157Institute of Anatomy, University of Bern, Bern, Switzerland
| | - Daniel Sedding
- grid.9018.00000 0001 0679 2801Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Martin-Luther-University Halle (Saale), Halle (Saale), Germany
| | - Oliver Borst
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Ingo Eitel
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Christian M. Karsten
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Robert Feil
- grid.10392.390000 0001 2190 1447Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - Bernd Pichler
- grid.10392.390000 0001 2190 1447Institute for Preclinical Imaging, Eberhard Karls University, Tübingen, Germany
| | - Jeanette Erdmann
- grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.4562.50000 0001 0057 2672Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Admar Verschoor
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
| | - Emmanouil Chavakis
- grid.411088.40000 0004 0578 8220Department for Internal Medicine III/Cardiology, University Hospital of the Johann-Wolfgang Goethe University, Frankfurt am Main, Germany
| | - Triantafyllos Chavakis
- grid.4488.00000 0001 2111 7257Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Philipp von Hundelshausen
- grid.5252.00000 0004 1936 973XInstitute for Cardiovascular Prevention, Ludwig Maximilians University Munich, Munich, Germany
| | - Jörg Köhl
- grid.4562.50000 0001 0057 2672Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany ,grid.239573.90000 0000 9025 8099Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
| | - Meinrad Gawaz
- grid.10392.390000 0001 2190 1447University Hospital, Department of Cardiovascular Medicine, Eberhard Karls University, Tübingen, Germany
| | - Harald F. Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany ,grid.452396.f0000 0004 5937 5237DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany ,grid.412468.d0000 0004 0646 2097University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
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34
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Xiong Z, Wang Q, Li W, Huang L, Zhang J, Zhu J, Xie B, Wang S, Kuang H, Lin X, Lee C, Kumar A, Li X. Platelet-Derived Growth Factor-D Activates Complement System to Propagate Macrophage Polarization and Neovascularization. Front Cell Dev Biol 2021; 9:686886. [PMID: 34150781 PMCID: PMC8207142 DOI: 10.3389/fcell.2021.686886] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/10/2021] [Indexed: 11/17/2022] Open
Abstract
Platelet-derived growth factor-D (PDGF-D) is highly expressed in immune cells. However, the potential role of PDGF-D in immune system remains thus far unclear. Here, we reveal a novel function of PDGF-D in activating both classical and alternative complement pathways that markedly increase chemokine and cytokine responses to promote macrophage polarization. Pharmacological targeting of the complement C3a receptor using SB290157 alleviated PDGF-D-induced neuroinflammation by blocking macrophage polarization and inhibited pathological choroidal neovascularization. Our study thus suggests that therapeutic strategies targeting both PDGF-D and the complement system may open up new possibilities for the treatment of neovascular diseases.
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Affiliation(s)
- Zhen Xiong
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qianqian Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wanhong Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lijuan Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jianing Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Juanhua Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Bingbing Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shasha Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Haiqing Kuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xianchai Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Chunsik Lee
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Anil Kumar
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuri Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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35
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Götz P, Braumandl A, Kübler M, Kumaraswami K, Ishikawa-Ankerhold H, Lasch M, Deindl E. C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue. Int J Mol Sci 2021; 22:5800. [PMID: 34071589 PMCID: PMC8198161 DOI: 10.3390/ijms22115800] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3-/-) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3-/- mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3-/- mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3-/- mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.
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Affiliation(s)
- Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Anna Braumandl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Konda Kumaraswami
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Department of Internal Medicine I, Faculty of Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (P.G.); (A.B.); (M.K.); (K.K.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Faculty of Medicine, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
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de Jong S, Gagliardi G, Garanto A, de Breuk A, Lechanteur YTE, Katti S, van den Heuvel LP, Volokhina EB, den Hollander AI. Implications of genetic variation in the complement system in age-related macular degeneration. Prog Retin Eye Res 2021; 84:100952. [PMID: 33610747 DOI: 10.1016/j.preteyeres.2021.100952] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 12/23/2022]
Abstract
Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.
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Affiliation(s)
- Sarah de Jong
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Giuliana Gagliardi
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Alejandro Garanto
- Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Pediatrics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Anita de Breuk
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Yara T E Lechanteur
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Suresh Katti
- Gemini Therapeutics Inc., Cambridge, MA, 02139, USA
| | - Lambert P van den Heuvel
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Laboratory Medicine, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Elena B Volokhina
- Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Amalia Children's Hospital, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Laboratory Medicine, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands
| | - Anneke I den Hollander
- Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands; Department of Human Genetics, Radboud University Medical Center, 6525, GA, Nijmegen, the Netherlands.
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Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration. Int J Mol Sci 2020; 21:ijms21249752. [PMID: 33371261 PMCID: PMC7765894 DOI: 10.3390/ijms21249752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 12/16/2022] Open
Abstract
Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD. The aim of this review is to (i) reflect on the possible complement targets in the context of wAMD pathology, (ii) investigate the results of prior clinical trials with complement inhibitors for wAMD patients, and (iii) outline important considerations when developing a future strategy for the treatment of wAMD.
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The Role of Complement in Angiogenesis. Antibodies (Basel) 2020; 9:antib9040067. [PMID: 33271774 PMCID: PMC7709120 DOI: 10.3390/antib9040067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 12/16/2022] Open
Abstract
The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy.
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Olson KN, Reijnders D, Gomes VCL, Hebert RC, Liu CC, Stephens JM, Redman LM, Douglas NC, Sones JL. Complement in Reproductive White Adipose Tissue Characterizes the Obese Preeclamptic-Like BPH/5 Mouse Prior to and During Pregnancy. BIOLOGY 2020; 9:E304. [PMID: 32971873 PMCID: PMC7564206 DOI: 10.3390/biology9090304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 12/23/2022]
Abstract
Preeclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by abnormal placental development with an unknown etiology. To better understand which women will develop PE, a number of maternal risk factors have been identified, including obesity. Visceral white adipose tissue (WAT) contains inflammatory mediators that may contribute to PE. To explore this, we utilized the blood pressure high (BPH)/5 mouse model of superimposed PE that spontaneously recapitulates the maternal PE syndrome. We hypothesized that BPH/5 visceral WAT adjacent to the female reproductive tract (reproductive WAT) is a source of complement factors that contribute to the inflammatory milieu and angiogenic imbalance at the maternal-fetal interface in this model and in preeclamptic women. To test our hypothesis, we calorie-restricted BPH/5 females for two weeks prior to pregnancy and the first seven days of pregnancy, which attenuated complement component 3 (C3) but not complement factor B, nor complement factor D, (adipsin) in the reproductive WAT or the implantation site in BPH/5. Furthermore, calorie restriction during pregnancy restored vascular endothelial and placental growth factor mRNA levels in the BPH/5 implantation site. These data show maternal reproductive WAT may be a source of increased C3 during pregnancy, which is increased at the maternal-fetal interface in preeclamptic BPH/5 mice. It also suggests that calorie restriction could regulate inflammatory mediators thought to contribute to placental dysfunction in PE. Future studies are necessary to examine the effect of calorie restriction on C3 throughout pregnancy and the role of maternal obesity in PE.
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Affiliation(s)
- Kelsey N. Olson
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (K.N.O.); (D.R.); (V.C.L.G.); (C.-C.L.)
- Reproductive Endocrinology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; (R.C.H.); (L.M.R.)
| | - Dorien Reijnders
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (K.N.O.); (D.R.); (V.C.L.G.); (C.-C.L.)
- Reproductive Endocrinology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; (R.C.H.); (L.M.R.)
| | - Viviane C. L. Gomes
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (K.N.O.); (D.R.); (V.C.L.G.); (C.-C.L.)
| | - R. Caitlin Hebert
- Reproductive Endocrinology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; (R.C.H.); (L.M.R.)
| | - Chin-Chi Liu
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (K.N.O.); (D.R.); (V.C.L.G.); (C.-C.L.)
| | - Jacqueline M. Stephens
- Adipocyte Biology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA;
| | - Leanne M. Redman
- Reproductive Endocrinology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; (R.C.H.); (L.M.R.)
| | - Nataki C. Douglas
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Women’s Health, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA;
| | - Jennifer L. Sones
- Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; (K.N.O.); (D.R.); (V.C.L.G.); (C.-C.L.)
- Reproductive Endocrinology Laboratory, Louisiana State University-Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA; (R.C.H.); (L.M.R.)
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Atherosclerotic Pre-Conditioning Affects the Paracrine Role of Circulating Angiogenic Cells Ex-Vivo. Int J Mol Sci 2020; 21:ijms21155256. [PMID: 32722151 PMCID: PMC7432497 DOI: 10.3390/ijms21155256] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022] Open
Abstract
In atherosclerosis, circulating angiogenic cells (CAC), also known as early endothelial progenitor cells (eEPC), are thought to participate mainly in a paracrine fashion by promoting the recruitment of other cell populations such as late EPC, or endothelial colony-forming cells (ECFC), to the injured areas. There, ECFC replace the damaged endothelium, promoting neovascularization. However, despite their regenerative role, the number and function of EPC are severely affected under pathological conditions, being essential to further understand how these cells react to such environments in order to implement their use in regenerative cell therapies. Herein, we evaluated the effect of direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. By using a quantitative proteomics approach, 194 altered proteins were identified in the secretome of pre-conditioned CAC, many of them related to inhibition of angiogenesis (e.g., endostatin, thrombospondin-1, fibulins) and cell migration. Functional assays corroborated that healthy CAC released factors enhanced ECFC angiogenesis, but, after atherosclerotic pre-conditioning, the secretome of pre-stimulated CAC negatively affected ECFC migration, as well as their ability to form tubules on a basement membrane matrix assay. Overall, we have shown here, for the first time, the effect of atherosclerotic factors over the paracrine role of CAC ex vivo. The increased release of angiogenic inhibitors by CAC in response to atherosclerotic factors induced an angiogenic switch, by blocking ECFC ability to form tubules in response to pre-conditioned CAC. Thus, we confirmed here that the angiogenic role of CAC is highly affected by the atherosclerotic environment.
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Effects of the Bone/Bone Marrow Microenvironments on Prostate Cancer Cells and CD59 Expression. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2753414. [PMID: 32337233 PMCID: PMC7165328 DOI: 10.1155/2020/2753414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 02/02/2020] [Accepted: 02/21/2020] [Indexed: 11/17/2022]
Abstract
Objective To evaluate the effects of human bone marrow mesenchymal stem cells (hBMSCs) and osteoblasts (hFOB1.19) on PC3 prostate cancer cells. Methods To simulate the in vivo interaction between the bone/bone marrow microenvironments and prostate cancer cells, we established cocultures of PC3 cells with hBMSC or hFOB1.19 cells and evaluated their effects on the proliferation, cell cycle distribution, cell migration, and invasion of PC3 cells. Quantitative reverse transcription polymerase chain reaction was used to detect CD59 mRNA expression in PC3 cells. The expression of receptor activator of nuclear factor- (NF-) κB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), CD59, NF-κB (p50 subunit), and cyclin D1 in PC3 cells was analyzed by immunofluorescence and western blotting. Results hBMSCs and hFOB1.19 cells enhanced the proliferation, migration, and invasion of PC3 cells; increased the proportion of PC3 cells in the S and G2/M phases of the cell cycle; and upregulated RANK, RANKL, OPG, CD59, cyclin D1, and NF-κB (p50 subunit) expression by PC3 cells. The RANKL inhibitor, scutellarin, inhibited these effects in PC3-hFOB1.19 cocultures. Conclusion hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.
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Shahulhameed S, Vishwakarma S, Chhablani J, Tyagi M, Pappuru RR, Jakati S, Chakrabarti S, Kaur I. A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy. Front Immunol 2020; 11:154. [PMID: 32117292 PMCID: PMC7026189 DOI: 10.3389/fimmu.2020.00154] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/21/2020] [Indexed: 01/15/2023] Open
Abstract
The complement system plays a crucial role in retinal homeostasis. While the proteomic analysis of ocular tissues in diabetic retinopathy (DR) has shown the deposition of complement proteins, their exact role in the pathogenesis of DR is yet unclear. We performed a detailed investigation of the role of the complement system by evaluating the levels of major complement proteins including C3, C1q, C4b, Complement Factor B (CFB), and Complement Factor H (CFH) and their activated fragments from both the classical and alternative pathways in vitreous humor and serum samples from proliferative DR (PDR) patients and controls. Further, the expressions of complements and several other key pro- and anti-angiogenic genes in the serum and vitreous humor were analyzed in the blood samples of PDR and non-PDR (NPDR) patients along with controls without diabetes. We also assessed the pro-inflammatory cytokines and matrix metalloproteinases in the vitreous humor samples. There was a significant increase in C3 and its activated fragment C3bα' (110 kDa) along with a corresponding upregulation of CFH in the vitreous of PDR patients, which confirmed the increased activation of the alternative complement pathway in PDR. Likewise, a significant upregulation of angiogenic genes and downregulation of anti-angiogenic genes was seen in PDR and NPDR cases. Increased MMP9 activity and upregulation of inflammatory markers IL8 and sPECAM with a downregulation of anti-inflammatory marker IL-10 in PDR vitreous indicated the possible involvement of microglia in DR pathogenesis. Further, a significantly high C3 deposition in the capillary wall along with thickening of basement membranes and co-localization of CFH expression with CD11b+ve activated microglial cells in diabetic retina suggested microglia as a source of CFH in diabetic retina. The increased CFH levels could be a feedback mechanism for arresting excessive complement activation in DR eyes. A gradual increase of CFH and CD11b expression in retina with early to late changes in epiretinal membranes of DR patients indicated a major role for the alternative complement pathway in disease progression.
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Affiliation(s)
- Shahna Shahulhameed
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
| | - Sushma Vishwakarma
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
| | - Jay Chhablani
- Smt. Kanuri Santhamma Center for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India.,Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Mudit Tyagi
- Smt. Kanuri Santhamma Center for Vitreo Retinal Diseases, LV Prasad Eye Institute, Hyderabad, India
| | - Rajeev R Pappuru
- Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Saumya Jakati
- Ophthalmic Pathology Laboratory, LV Prasad Eye Institute, Hyderabad, India
| | | | - Inderjeet Kaur
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
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Sun M, Wadehra M, Casero D, Lin MC, Aguirre B, Parikh S, Matynia A, Gordon L, Chu A. Epithelial Membrane Protein 2 (EMP2) Promotes VEGF-Induced Pathological Neovascularization in Murine Oxygen-Induced Retinopathy. Invest Ophthalmol Vis Sci 2020; 61:3. [PMID: 32031575 PMCID: PMC7325623 DOI: 10.1167/iovs.61.2.3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 11/07/2019] [Indexed: 02/07/2023] Open
Abstract
Purpose Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs as a consequence of postnatal hyperoxia exposure in premature infants, resulting in vasoproliferation in the retina. The tetraspan protein epithelial membrane protein-2 (EMP2) is highly expressed in the retinal pigment epithelium (RPE) in adults, and it controls vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line. We, therefore, hypothesized that Emp2 knockout (Emp2 KO) protects against neovascularization in murine oxygen-induced retinopathy (OIR). Methods Eyes were obtained from wildtype (WT) and Emp2 KO mouse pups at P7, P12, P17, and P21 after normoxia or hyperoxia (P7-P12) exposure. Following hyperoxia exposure, RNA sequencing was performed using the retina/choroid layers obtained from WT and Emp2 KO at P17. Retinal sections from P7, P12, P17, and P21 were evaluated for Emp2, hypoxia-inducible factor 1α (Hif1α), and VEGF expression. Whole mount images were generated to assess vaso-obliteration at P12 and neovascularization at P17. Results Emp2 KO OIR mice demonstrated a decrease in pathologic neovascularization at P17 compared with WT OIR mice through evaluation of retinal vascular whole mount images. This protection was accompanied by a decrease in Hif1α at P12 and VEGFA expression at P17 in Emp2 KO animals compared with the WT animals in OIR conditions. Collectively, our results suggest that EMP2 enhances the effects of neovascularization through modulation of angiogenic signaling. Conclusions The protection of Emp2 KO mice against pathologic neovascularization through attenuation of HIF and VEGF upregulation in OIR suggests that hypoxia-induced upregulation of EMP2 expression in the neuroretina modulates HIF-mediated neuroretinal VEGF expression.
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Affiliation(s)
- Michel Sun
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - Madhuri Wadehra
- Department of Pathology Lab Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
- Jonsson Comprehensive Cancer, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - David Casero
- Department of Pathology Lab Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - Meng-Chin Lin
- Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - Brian Aguirre
- Department of Pathology Lab Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - Sachin Parikh
- Laboratory of Ocular and Molecular Biology and Genetics, Jules Stein Institute, University of California-Los Angeles, Los Angeles, California, United States
| | - Anna Matynia
- Laboratory of Ocular and Molecular Biology and Genetics, Jules Stein Institute, University of California-Los Angeles, Los Angeles, California, United States
| | - Lynn Gordon
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
| | - Alison Chu
- Division of Neonatology and Developmental Biology, Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California, United States
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Park YJ, Woo SJ, Kim YM, Hong S, Lee YE, Park KH. Immune and Inflammatory Proteins in Cord Blood as Predictive Biomarkers of Retinopathy of Prematurity in Preterm Infants. Invest Ophthalmol Vis Sci 2020; 60:3813-3820. [PMID: 31525777 DOI: 10.1167/iovs.19-27258] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To determine whether elevated levels of immune/inflammatory proteins in cord blood, alone or in combination with conventional clinical parameters, can predict the occurrence and progression of retinopathy of prematurity (ROP) in preterm infants. Methods This was a retrospective cohort study of 110 premature singleton infants who were born at ≤32.0 weeks. Cord plasma at birth was assayed for interleukin-6, C3a, C5a, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1, macrophage colony-stimulating factor, endostatin, a proliferation-inducing ligand, insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-2, and calcium-binding protein A8/A9 complex levels. The primary outcome measures were the occurrence of any stage ROP, severe ROP (>stage 3), and vision-threatening type 1 ROP requiring laser treatment. Results ROP was diagnosed in 30 of 110 infants (27.3%), including 14 (12.7%) with severe ROP. Laser treatment was performed on 7 infants (6.4%). Multiple logistic regression analyses indicated that elevated levels of cord plasma IL-6 were significantly associated with severe ROP, whereas elevated levels of cord plasma C5a were significantly associated with ROP laser treatments. However, none of the proteins measured in the cord plasma were associated with ROP occurrence. Using a stepwise regression procedure, we developed a combined prediction model, which included high cord plasma IL-6 levels and low birth weight for severe ROP (area under the curve [AUC], 0.840), and high cord plasma C5a levels and low birth weight for laser treatment (AUC, 0.884). Conclusions Elevated levels of cord plasma IL-6 and C5a could be used as independent markers to predict severe ROP and laser treatment, respectively, with combined models predicting ROP progression with good accuracy.
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Affiliation(s)
- Young Joo Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Ophthalmology, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Se Joon Woo
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yu Mi Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Subeen Hong
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Eun Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyo Hoon Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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Sauter RJ, Sauter M, Reis ES, Emschermann FN, Nording H, Ebenhöch S, Kraft P, Münzer P, Mauler M, Rheinlaender J, Madlung J, Edlich F, Schäffer TE, Meuth SG, Duerschmied D, Geisler T, Borst O, Gawaz M, Kleinschnitz C, Lambris JD, Langer HF. Functional Relevance of the Anaphylatoxin Receptor C3aR for Platelet Function and Arterial Thrombus Formation Marks an Intersection Point Between Innate Immunity and Thrombosis. Circulation 2019; 138:1720-1735. [PMID: 29802205 DOI: 10.1161/circulationaha.118.034600] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Platelets have distinct roles in the vascular system in that they are the major mediator of thrombosis, critical for restoration of tissue integrity, and players in vascular inflammatory conditions. In close spatiotemporal proximity, the complement system acts as the first line of defense against invading microorganisms and is a key mediator of inflammation. Whereas the fluid phase cross-talk between the complement and coagulation systems is well appreciated, the understanding of the pathophysiological implications of such interactions is still scant. METHODS We analyzed coexpression of the anaphylatoxin receptor C3aR with activated glycoprotein IIb/IIIa on platelets of 501 patients with coronary artery disease using flow cytometry; detected C3aR expression in human or murine specimen by polymerase chain reaction, immunofluorescence, Western blotting, or flow cytometry; and examined the importance of platelet C3aR by various in vitro platelet function tests, in vivo bleeding time, and intravital microscopy. The pathophysiological relevance of C3aR was scrutinized with the use of disease models of myocardial infarction and stroke. To approach underlying molecular mechanisms, we identified the platelet small GTPase Rap1b using nanoscale liquid chromatography coupled to tandem mass spectrometry. RESULTS We found a strong positive correlation of platelet complement C3aR expression with activated glycoprotein IIb/IIIa in patients with coronary artery disease and coexpression of C3aR with glycoprotein IIb/IIIa in thrombi obtained from patients with myocardial infarction. Our results demonstrate that the C3a/C3aR axis on platelets regulates distinct steps of thrombus formation such as platelet adhesion, spreading, and Ca2+ influx. Using C3aR-/- mice or C3-/- mice with reinjection of C3a, we uncovered that the complement activation fragment C3a regulates bleeding time after tail injury and thrombosis. Notably, C3aR-/- mice were less prone to experimental stroke and myocardial infarction. Furthermore, reconstitution of C3aR-/- mice with C3aR+/+ platelets and platelet depletion experiments demonstrated that the observed effects on thrombosis, myocardial infarction, and stroke were specifically caused by platelet C3aR. Mechanistically, C3aR-mediated signaling regulates the activation of Rap1b and thereby bleeding arrest after injury and in vivo thrombus formation. CONCLUSIONS Overall, our findings uncover a novel function of the anaphylatoxin C3a for platelet function and thrombus formation, highlighting a detrimental role of imbalanced complement activation in cardiovascular diseases.
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Affiliation(s)
- Reinhard J Sauter
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany.,Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Manuela Sauter
- Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Edimara S Reis
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia (E.S.R., J.D.L.)
| | - Frederic N Emschermann
- Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Henry Nording
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany.,Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Sonja Ebenhöch
- Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Peter Kraft
- Department of Neurology, University of Würzburg, Germany (P.K.)
| | - Patrick Münzer
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Maximilian Mauler
- Cardiology and Angiology I, Heart Center Freiburg University and Faculty of Medicine (M.M., D.D.), University of Freiburg, Germany
| | - Johannes Rheinlaender
- Institute of Applied Physics (J.R., T.E.S.), Eberhard Karls-University Tübingen, Germany
| | - Johannes Madlung
- Proteom Center, Interfaculty Institute for Cell Biology (J.M.), Eberhard Karls-University Tübingen, Germany
| | - Frank Edlich
- Institute of Biochemistry (F.E.), University of Freiburg, Germany.,Institute for Biochemistry and Molecular Biology, University of Freiburg, Germany (F.E.).,BIOSS, Centre for Biological Signaling Studies, University of Freiburg, Germany (F.E.)
| | - Tilman E Schäffer
- Institute of Applied Physics (J.R., T.E.S.), Eberhard Karls-University Tübingen, Germany
| | - Sven G Meuth
- Department of Neurology, University of Münster, Germany (S.G.M.)
| | - Daniel Duerschmied
- Cardiology and Angiology I, Heart Center Freiburg University and Faculty of Medicine (M.M., D.D.), University of Freiburg, Germany
| | - Tobias Geisler
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Oliver Borst
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | - Meinrad Gawaz
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany
| | | | - John D Lambris
- Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia (E.S.R., J.D.L.)
| | - Harald F Langer
- Department of Cardiology and Cardiovascular Medicine, University Clinic (R.J.S., H.N., P.M., T.G., O.B., M.G., H.F.L.), Eberhard Karls-University Tübingen, Germany.,Section for Cardioimmunology (R.J.S., M.S., F.N.E., H.N., S.E., H.F.L.), Eberhard Karls-University Tübingen, Germany
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Burwick RM, Togioka BM, Speranza RJ, Gaffney JE, Roberts VHJ, Frias AE, Rincón M. Assessment of blood-brain barrier integrity and neuroinflammation in preeclampsia. Am J Obstet Gynecol 2019; 221:269.e1-269.e8. [PMID: 31229428 DOI: 10.1016/j.ajog.2019.06.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 06/05/2019] [Accepted: 06/12/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Although blood-brain barrier integrity is intact under normal pregnancy conditions, animal studies suggest that blood-brain barrier impairment occurs in preeclampsia. Yet, human data are limited, and the integrity of the blood-brain barrier has not been assessed in women with preeclampsia. OBJECTIVE We sought to test the hypothesis that the integrity of the blood-brain barrier is impaired and that neuroinflammation is increased in women with preeclampsia. STUDY DESIGN We performed an observational case-control study in pregnant women >24 weeks gestation who underwent spinal anesthesia for elective cesarean delivery or combined spinal epidural analgesia for labor. Cases were women with preeclampsia, and control subjects were women with either healthy pregnancy, chronic hypertension, or gestational hypertension. Paired samples of blood, urine, and cerebrospinal fluid were collected from each subject before delivery. We measured albumin, C5a, C5b-9, tumor necrosis factor-α, and interleukin-6 concentrations in plasma and cerebrospinal fluid, and albumin, C5a, and C5b-9 concentrations in urine, using colorimetric or enzyme-linked immunosorbent assays. The ratio of albumin in cerebrospinal fluid to plasma (Qalb) was used as a surrogate for maternal blood-brain barrier integrity. Cerebrospinal fluid concentrations of C5a, C5b-9, tumor necrosis factor-α, and interleukin-6 were used as surrogate markers of neuroinflammation. Differences in Qalb and cerebrospinal fluid protein concentrations between groups were assessed by nonparametric test of medians. RESULTS Forty-eight subjects were enrolled, which included 16 cases with preeclampsia, 16 control subjects with healthy pregnancy, and 16 control subjects with either chronic or gestational hypertension. Qalb values were not increased in preeclampsia cases compared with healthy or hypertensive control subjects (Qalb median, 3.5 [interquartile range, 2.9-5.1] vs 3.9 [interquartile range, 3.0-4.8] vs 3.9 [interquartile range, 3.0-4.8]; P=.78]. Moreover, Qalb values were not increased in the subset of women with preeclampsia with severe features (n=8) compared with those without severe features (n=8; Qalb median, 3.5 [interquartile range, 3.3-4.9] vs 3.7 [interquartile range, 2.3-5.5]; P=.62]. Cerebrospinal fluid concentrations of C5a, C5b-9, tumor necrosis factor-α and interleukin-6 were not increased in cases of preeclampsia, compared with control subjects with either healthy pregnancy, chronic hypertension, or gestational hypertension (P>.05, all comparisons). In contrast to the negative findings in cerebrospinal fluid, plasma concentrations of both C5b-9 and interleukin-6 and urine concentrations of C5a and C5b-9 were increased in cases of preeclampsia. CONCLUSION Through measurements of albumin, complement proteins, and cytokines in paired samples of blood and cerebrospinal fluid at the time of delivery, we found no evidence of blood-brain barrier impairment or neuroinflammation in preeclampsia. Larger studies that will investigate a wider range of proteins are suggested to validate our findings.
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Affiliation(s)
- Richard M Burwick
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
| | - Brandon M Togioka
- Department of Anesthesia and Perioperative Medicine, Oregon Health & Science University, Portland, OR
| | - Rosa J Speranza
- School of Medicine, Oregon Health & Science University, Portland, OR
| | - Jessica E Gaffney
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR
| | - Victoria H J Roberts
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR
| | - Antonio E Frias
- Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR; Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Oregon Health & Science University, Portland, OR
| | - Mónica Rincón
- Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Oregon Health & Science University, Portland, OR
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Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology 2019; 127:186-195. [PMID: 31474439 DOI: 10.1016/j.ophtha.2019.07.011] [Citation(s) in RCA: 371] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 06/27/2019] [Accepted: 07/09/2019] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS Two hundred forty-six patients with GA. METHODS Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.
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Comparative transcriptome analysis of peripheral blood mononuclear cells in renal transplant recipients in everolimus- and tacrolimus-based immunosuppressive therapy. Eur J Pharmacol 2019; 859:172494. [PMID: 31238062 DOI: 10.1016/j.ejphar.2019.172494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 06/21/2019] [Accepted: 06/21/2019] [Indexed: 12/19/2022]
Abstract
To better define the biological impact of immunosuppression on peripheral blood mononuclear cells (PBMC), we employed RNASeq analysis to compare the whole transcriptomic profile of a group of renal transplant recipients undergoing maintenance treatment with Everolimus (EVE) with those treated with Tacrolimus (TAC). Then, obtained results were validated by classical biomolecular methodologies. The statistical analysis allowed the identification of four genes discriminating the 2 study groups: Sushi Domain Containing 4 (SUSD4, P = 0.02), T Cell Leukemia/Lymphoma 1A (TCL1A, P = 0.02), adhesion G protein-coupled receptor E3 (ADGRE3, P = 0.01), Immunoglobulin Heavy Constant Gamma 3 (IGHG3, P = 0.03). All of them were significantly down-regulated in patients treated with EVE compared to TAC. The Area under Receiver Operating Characteristic (AUROC) of the final model based on these 4 genes was 73.1% demonstrating its good discriminative power. RT-PCR and ELISA validated transcriptomic results. Additionally, an in vitro model confirmed that EVE significantly down-regulates (P<0.001) TCL1A, SUSD4, ADGRE3 and IgHG3 in PBMCs as well as in T cells and monocytes isolated from healthy subjects. Taken together, our data, revealed, for the first time, a new four gene-based transcriptomic fingerprint down-regulated by EVE in PBMCs of renal transplant patients that could improve the available knowledge regarding some of the biological/cellular effects of the mTOR-Is (including their antineoplastic and immune-regulatory properties).
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Geller A, Yan J. The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy. Front Immunol 2019; 10:1074. [PMID: 31164885 PMCID: PMC6536589 DOI: 10.3389/fimmu.2019.01074] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 04/26/2019] [Indexed: 12/17/2022] Open
Abstract
It has long been understood that the control and surveillance of tumors within the body involves an intricate dance between the adaptive and innate immune systems. At the center of the interplay between the adaptive and innate immune response sits the complement system—an evolutionarily ancient response that aids in the destruction of microorganisms and damaged cells, including cancer cells. Membrane-bound complement regulatory proteins (mCRPs), such as CD46, CD55, and CD59, are expressed throughout the body in order to prevent over-activation of the complement system. These mCRPs act as a double-edged sword however, as they can also over-regulate the complement system to the extent that it is no longer effective at eliminating cancerous cells. Recent studies are now indicating that mCRPs may function as a biomarker of a malignant transformation in numerous cancer types, and further, are being shown to interfere with anti-tumor treatments. This highlights the critical roles that therapeutic blockade of mCRPs can play in cancer treatment. Furthermore, with the complement system having the ability to both directly and indirectly control adaptive T-cell responses, the use of a combinatorial approach of complement-related therapy along with other T-cell activating therapies becomes a logical approach to treatment. This review will highlight the biomarker-related role that mCRP expression may have in the classification of tumor phenotype and predicted response to different anti-cancer treatments in the context of an emerging understanding that complement activation within the Tumor Microenvironment (TME) is actually harmful for tumor control. We will discuss what is known about complement activation and mCRPs relating to cancer and immunotherapy, and will examine the potential for combinatorial approaches of anti-mCRP therapy with other anti-tumor therapies, especially checkpoint inhibitors such as anti PD-1 and PD-L1 monoclonal antibodies (mAbs). Overall, mCRPs play an essential role in the immune response to tumors, and understanding their role in the immune response, particularly in modulating currently used cancer therapeutics may lead to better clinical outcomes in patients with diverse cancer types.
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Affiliation(s)
- Anne Geller
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, United States
| | - Jun Yan
- Immuno-Oncology Program, Department of Medicine, The James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, United States
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Zasada M, Suski M, Bokiniec R, Szwarc-Duma M, Borszewska-Kornacka MK, Madej J, Bujak-Gizycka B, Madetko-Talowska A, Revhaug C, Baumbusch LO, Saugstad OD, Pietrzyk JJ, Kwinta P. An iTRAQ-Based Quantitative Proteomic Analysis of Plasma Proteins in Preterm Newborns With Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 2019; 59:5312-5319. [PMID: 30398622 DOI: 10.1167/iovs.18-24914] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Retinopathy of prematurity (ROP) is a vision-threatening complication of a premature birth, in which the etiology still remains unclear. Importantly, the molecular processes that govern these effects can be investigated in a perturbed plasma proteome composition. Thus, plasma proteomics may add new insights into a better understanding of the pathogenesis of this disease. Methods The cord and peripheral blood of neonates (≤30 weeks gestational age) was drawn at birth and at the 36th postmenstrual week (PMA), respectively. Blood samples were retrospectively subdivided into ROP(+) and ROP(-) groups, according to the development of ROP. Results The quantitative analysis of plasma proteome at both time points revealed 30 protein abundance changes between ROP(+) and ROP(-) groups. After standardization to gestational age, children who developed ROP were characterized by an increased C3 complement component and fibrinogen level at both analyzed time points. Conclusions Higher levels of the complement C3 component and fibrinogen, present in the cord blood and persistent to 36 PMA, may indicate a chronic low-grade systemic inflammation and hypercoagulable state that may play a role in the development of ROP.
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Affiliation(s)
- Magdalena Zasada
- Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Maciej Suski
- Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Renata Bokiniec
- Neonatal and Intensive Care Department, Medical University of Warsaw, Warsaw, Poland
| | - Monika Szwarc-Duma
- Neonatal and Intensive Care Department, Medical University of Warsaw, Warsaw, Poland
| | | | - Józef Madej
- Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Beata Bujak-Gizycka
- Chair of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Madetko-Talowska
- Department of Medical Genetics, Jagiellonian University Medical College, Krakow, Poland
| | - Cecilie Revhaug
- Department of Pediatric Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Lars O Baumbusch
- Department of Pediatric Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Ola D Saugstad
- Department of Pediatric Research, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Jacek Józef Pietrzyk
- Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Przemko Kwinta
- Department of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
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