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Chen Q, Li D, Zheng Y, Li X, Wang L, Li W, Lu Z, Wang F, Zhou L. The Maternal-Fetal Interface Fibrin Deposition and Expression of FGL2 in the Placenta of Preeclampsia and Fetal Growth Restriction. Int J Gynecol Pathol 2025:00004347-990000000-00241. [PMID: 40388520 DOI: 10.1097/pgp.0000000000001095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2025]
Abstract
We aimed to assess fibrin deposition in placentas of patients with preeclampsia (PE) with fetal growth restriction (FGR) and the relationship with fibrinogen-like protein 2 (FGL2). In this case-control study, pregnant women with PE (n=48), PE with FGR (n=44), FGR (n=43), and healthy pregnant women (n=43) at term gestation were recruited. We compared the baseline characteristics, blood coagulation parameters, and placenta characteristics. Masson's trichrome staining was used to categorize 2 types of fibrinoid. FGL2 expression was examined by immunohistochemical staining. The PE+FGR placentas showed more obvious fetal and maternal vascular malperfusion and maternal-fetal interface fibrin deposition when compared with the others. Increased fibrin-type and matrix-type fibrinoids were found in the placenta of the PE+FGR group when compared with the controls. FGL2 was localized in the junction of these 2 types of fibrinoid, as well as extravillous trophoblastic layers and decidual stromal cells. The PE+FGR group had significantly lower FGL2 expression levels. Placental vascular malperfusion with massive maternal-fetal interface fibrin deposition was found in PE with FGR. We report the characteristic colocalization of 2 types of placental fibrinoid deposition and FGL2 immunoreactivity and, therefore, help in elucidating the mechanisms in the pathology of PE with FGR.
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Affiliation(s)
- Qihui Chen
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Donglu Li
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Yushuang Zheng
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Xinran Li
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Lu Wang
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Wangzhi Li
- School of Stomatology, Wenzhou Medical University
| | - Zheyu Lu
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Fan Wang
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- The Second Clinical Medical College of Wenzhou Medical University
| | - Lingling Zhou
- Departments of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
- Departments of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou City, China
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Wang Y, Wang M, Kang J, Zhang Y. Role of fibrinogen-like 2 (FGL2) proteins in implantation: Potential implications and mechanism. Gene 2025; 946:149284. [PMID: 39884406 DOI: 10.1016/j.gene.2025.149284] [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: 08/12/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
Fibrinogen-like (Fgl2) protein belongs to fibrinogen super family, which catalyzes the conversion of prothrombin to thrombin and is involved in the coagulation process. There are two different forms of functional Fgl2 protein: membrane associated Fgl2 (mFgl2) and soluble Fgl2 (sFgl2). mFgl2, as a type II transmembrane protein with property with prothrombinase activity from its N-terminal fragment, was extensively secreted or expressed by inflammatory macrophages, dendritic cells (DCs), Th1 cells and endothelial cells. While sFgl2 was mainly produced by regulatory T cells (Tregs) and then secreted into the vasculature, which contributes to autoimmune disease by regulating maturation of (DCs), polarization of macrophage, inhibiting T cell proliferation and differentiation and inducing apoptosis of B cells. In particular, emerging evidence has shown that Fgl2 is implicated in female reproductive system that contributes to embryo development, ovarian granulosa cells differentiation and implantation failure. This article summarizes the role and potential mechanisms of Fgl2 in reproduction and identifies research gaps along with the future directions.
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Affiliation(s)
- Yueying Wang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China; Department of Reproductive Medicine, Jining No.1 People's Hospital, Jining 272002, China; Key Laboratory of Pregnancy Disorder Research of Jining, 272002, China
| | - Mei Wang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China
| | - Jiawei Kang
- Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China; Department of Obstetrical, Zhongnan Hospital of Wuhan University, Wuhan 430062, China
| | - Yuanzhen Zhang
- Center for Reproductive Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430062, China; Clinical Medicine Research Center of Prenatal Diagnosis and Birth Health in Hubei Province, Wuhan, Hubei 430062, China.
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Morris AB, Adelman MW, Bennion KB, Martinez CD, McCook KM, Woodworth MH, Langelier CR, Rouphael N, Scharer CD, Maier CL, Kraft CS, Ford ML. Fgl2 regulates FcγRIIB+CD8+ T cell responses during infection. JCI Insight 2025; 10:e186259. [PMID: 40197366 PMCID: PMC11981615 DOI: 10.1172/jci.insight.186259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 02/12/2025] [Indexed: 04/10/2025] Open
Abstract
While the inhibitory receptor FcγRIIB has been shown to be upregulated on activated CD8+ T cells in both mice and humans, its effect on T cell fate during infection has not been fully elucidated. We identified an increase in FcγRIIB-expressing CD8+ T cells in patients with COVID-19 relative to healthy controls as well as in mouse models of viral infection. Despite its well-known role as an Fc receptor, FcγRIIB also ligates the immunosuppressive cytokine Fgl2, resulting in CD8+ T cell apoptosis. Both chronic LCMV infection in mice and COVID-19 in humans resulted in a significant increase in plasma Fgl2. Transfer of CD8+ T cells into a Fgl2-replete, but not Fgl2-devoid, environment resulted in elimination of FcγRIIB+, but not FcγRIIB-, CD8+ T cells. Similarly, plasma Fgl2 was directly proportional to CD8+ T cell lymphopenia in patients with COVID-19. RNA-Seq analysis demonstrated that Fgl2 was produced by murine virus-specific CD8+ T cells, with an increase in Fgl2 in CD8+ T cells elicited during chronic versus acute viral infection. Fgl2 was also upregulated in CD8+ T cells from patients with COVID-19 versus healthy controls. In summary, CD8+ T cell production of Fgl2 during viral infection underpinned an FcγRIIB-mediated loss of CD8+ T cell immunity in both mice and humans.
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Affiliation(s)
| | - Max W. Adelman
- Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA
| | | | | | | | - Michael H. Woodworth
- Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA
| | - Charles R. Langelier
- Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, California, USA
| | - Nadine Rouphael
- Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA
| | | | - Cheryl L. Maier
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Colleen S. Kraft
- Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, USA
| | - Mandy L. Ford
- Department of Surgery and Emory Transplant Center and
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4
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Wang C, Sun H, Wang R, Ma X, Sun Y. FGL2: A new target molecule for coagulation and immune regulation in infectious disease. Int Immunopharmacol 2024; 143:113505. [PMID: 39488038 DOI: 10.1016/j.intimp.2024.113505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024]
Abstract
Infectious diseases are complex inflammatory-immunologic host responses caused by various pathogens, such as viruses, bacteria, parasites, and fungi. In the process of infectious disease development, immune cells are activated, and a substantial number of inflammatory factors are released within the endothelium, which results in coagulation activation and the formation of intravascular thrombi. Furthermore, infection-induced hypercoagulability amplifies the inflammatory response and immune dysregulation. Emerging evidence suggests that fibrinogen-like protein 2 (FGL2) has a crucial role in facilitating procoagulant, pro-inflammatory, and immune-regulatory responses in various infectious diseases. This review illustrates the complex procoagulation and immunoregulatory roles of FGL2, suggesting it could be a target for novel immune interventions in intractable infectious diseases.
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Affiliation(s)
- Chaoyang Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - He Sun
- Department of Hepatobiliary Surgery and Transplantation, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China
| | - Rui Wang
- Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaochun Ma
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yini Sun
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.
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Chen J, Wu L, Li Y. FGL1 and FGL2: emerging regulators of liver health and disease. Biomark Res 2024; 12:53. [PMID: 38816776 PMCID: PMC11141035 DOI: 10.1186/s40364-024-00601-0] [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: 04/23/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024] Open
Abstract
Liver disease is a complex group of diseases with high morbidity and mortality rates, emerging as a major global health concern. Recent studies have highlighted the involvement of fibrinogen-like proteins, specifically fibrinogen-like protein 1 (FGL1) and fibrinogen-like protein 2 (FGL2), in the regulation of various liver diseases. FGL1 plays a crucial role in promoting hepatocyte growth, regulating lipid metabolism, and influencing the tumor microenvironment (TME), contributing significantly to liver repair, non-alcoholic fatty liver disease (NAFLD), and liver cancer. On the other hand, FGL2 is a multifunctional protein known for its role in modulating prothrombin activity and inducing immune tolerance, impacting viral hepatitis, liver fibrosis, hepatocellular carcinoma (HCC), and liver transplantation. Understanding the functions and mechanisms of fibrinogen-like proteins is essential for the development of effective therapeutic approaches for liver diseases. Additionally, FGL1 has demonstrated potential as a disease biomarker in radiation and drug-induced liver injury as well as HCC, while FGL2 shows promise as a biomarker in viral hepatitis and liver transplantation. The expression levels of these molecules offer exciting prospects for disease assessment. This review provides an overview of the structure and roles of FGL1 and FGL2 in different liver conditions, emphasizing the intricate molecular regulatory processes and advancements in targeted therapies. Furthermore, it explores the potential benefits and challenges of targeting FGL1 and FGL2 for liver disease treatment and the prospects of fibrinogen-like proteins as biomarkers for liver disease, offering insights for future research in this field.
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Affiliation(s)
- Jiongming Chen
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Lei Wu
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of Medicine, Chongqing University, Chongqing, 400030, China.
- Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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Djalali-Cuevas A, Rettel M, Stein F, Savitski M, Kearns S, Kelly J, Biggs M, Skoufos I, Tzora A, Prassinos N, Diakakis N, Zeugolis DI. Macromolecular crowding in human tenocyte and skin fibroblast cultures: A comparative analysis. Mater Today Bio 2024; 25:100977. [PMID: 38322661 PMCID: PMC10846491 DOI: 10.1016/j.mtbio.2024.100977] [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: 10/04/2023] [Revised: 12/22/2023] [Accepted: 01/24/2024] [Indexed: 02/08/2024] Open
Abstract
Although human tenocytes and dermal fibroblasts have shown promise in tendon engineering, no tissue engineered medicine has been developed due to the prolonged ex vivo time required to develop an implantable device. Considering that macromolecular crowding has the potential to substantially accelerate the development of functional tissue facsimiles, herein we compared human tenocyte and dermal fibroblast behaviour under standard and macromolecular crowding conditions to inform future studies in tendon engineering. Basic cell function analysis made apparent the innocuousness of macromolecular crowding for both cell types. Gene expression analysis of the without macromolecular crowding groups revealed expression of tendon related molecules in human dermal fibroblasts and tenocytes. Protein electrophoresis and immunocytochemistry analyses showed significantly increased and similar deposition of collagen fibres by macromolecular crowding in the two cell types. Proteomics analysis demonstrated great similarities between human tenocyte and dermal fibroblast cultures, as well as the induction of haemostatic, anti-microbial and tissue-protective proteins by macromolecular crowding in both cell populations. Collectively, these data rationalise the use of either human dermal fibroblasts or tenocytes in combination with macromolecular crowding in tendon engineering.
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Affiliation(s)
- Adrian Djalali-Cuevas
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, Arta, Greece
- School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
| | - Mandy Rettel
- Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Frank Stein
- Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Mikhail Savitski
- Proteomics Core Facility, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | | | - Jack Kelly
- Galway University Hospital, Galway, Ireland
| | - Manus Biggs
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, University of Galway, Galway, Ireland
| | - Ioannis Skoufos
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, Arta, Greece
| | - Athina Tzora
- Laboratory of Animal Science, Nutrition and Biotechnology, School of Agriculture, University of Ioannina, Arta, Greece
| | - Nikitas Prassinos
- School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Diakakis
- School of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios I. Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), Charles Institute of Dermatology, Conway Institute of Biomolecular & Biomedical Research and School of Mechanical & Materials Engineering, University College Dublin (UCD), Dublin, Ireland
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7
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Hu X, Wan X, Diao Y, Shen Z, Zhang Z, Wang P, Hu D, Wang X, Yan W, Yu C, Luo X, Wang H, Ning Q. Fibrinogen-like protein 2 regulates macrophage glycolytic reprogramming by directly targeting PKM2 and exacerbates alcoholic liver injury. Int Immunopharmacol 2023; 124:110957. [PMID: 37734200 DOI: 10.1016/j.intimp.2023.110957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND & AIMS Switching of the macrophage activation phenotype affects the pathogenesis of alcoholic liver diseases, and metabolic reprogramming can provide the energy demand for macrophage phenotypes shift. However, the molecular mechanism by which immune metabolism regulates the activation of proinflammatory macrophages remains unclear. APPROACH Expression of Fgl2 was examined in patients with alcoholic hepatitis and healthy controls. Mice were fed with a Lieber-DeCarli diet. Livers from mice were used to observe liver injury and macrophage activation. Fgl2 overexpressing THP-1 cell was used to find interacting partners through immunoprecipitation plus mass spectrometry. Naive bone marrow derived macrophages stimulated with LPS and ethanol were used for cell experiments. RESULTS Expression of Fgl2 was elevated in macrophages of livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Fgl2 depletion ameliorated ethanol diet-induced hepatic steatosis and oxidative injury as well as the levels of proinflammatory cytokines. Fgl2-/- mice exhibited suppressed M1 polarization and glycolysis pathway activation. Fgl2 interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and facilitated PKM2 nuclear translocation, thus promoting glycolysis in M1 macrophages and the secretion of proinflammatory cytokines. Furthermore, Fgl2 overexpression in THP-1 cells enhances PKM2-dependent glycolysis and inflammation, which could be reversed by activation of enzymatic PKM2 using DASA58. CONCLUSIONS Taken together, Fgl2 hastens the development of alcoholic liver injury by mediating PKM2 dependent aerobic glycolysis in proinflammatory macrophages. Strategies that inhibiting proinflammatory macrophage activation by silencing Fgl2 might be a potential therapeutic intervention for alcoholic liver injury.
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Affiliation(s)
- Xue Hu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Xiaoyang Wan
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Yuting Diao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Zhe Shen
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongwei Zhang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Peng Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Danqin Hu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Xiaojing Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Weiming Yan
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Wuhan, China
| | - Hongwu Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China.
| | - Qin Ning
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China.
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Fu L, Liu Z, Liu Y. Fibrinogen-like protein 2 in inflammatory diseases: A future therapeutic target. Int Immunopharmacol 2023; 116:109799. [PMID: 36764282 DOI: 10.1016/j.intimp.2023.109799] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/09/2022] [Accepted: 01/25/2023] [Indexed: 02/10/2023]
Abstract
Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, exists as a membrane-bound protein with immune-associated coagulation activity and a soluble form possessing immunosuppressive functions. The immunomodulatory role of FGL2 is evident in fibrin deposition-associated inflammatory diseases and cancer, suggesting that FGL2 expression could be exploited as a disease biomarker and a therapeutic target. Recently, in vitro studies and knockout and transgenic animal FGL2 models have been used by us and others to reveal the involvement of FGL2 in the pathogenesis of various inflammatory diseases. This review summarizes our current knowledge of the immunomodulatory role of FGL2 in inflammatory diseases and examines the role of FGL2 as a potential therapeutic target.
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Affiliation(s)
- Li Fu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
| | - Yang Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
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9
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Jiao S, Tan N, Zhu C, Fu Y, Zhang K, Ding Y, Xu W. The distinctive role of membrane fibrinogen-like protein 2 in the liver stage of rodent malaria infections. Parasite Immunol 2023; 45:e12956. [PMID: 36300695 DOI: 10.1111/pim.12956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 01/09/2023]
Abstract
Viral infection often induce the expression of murine fibrinogen-like protein 2 (mFGL2) triggering immune coagulation, which causes severe liver pathogenesis via increased fibrin deposition and thrombosis in the microvasculature. We aimed to investigate the role of mFGL2 in the liver stage of malaria infections. We reveal that infection with malaria sporozoites also induces increased expression of mFGL2 and that this expression is primarily located within the liver Kupffer and endothelial cells. In addition, we report that inhibition of FGL2 has no significant effect on immune coagulation but increases the expression of inflammatory cytokines in the livers of infected mice. Interestingly, FGL2 deficiency had no significant impact on the development of liver stage malaria parasites or the pathogenesis of the infected liver. In contrast to viral infections, we conclude that mFGL2 does not contribute to either parasite development or liver pathology during these infections, revealing the unique features of this protein in liver-stage malaria infections.
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Affiliation(s)
- Shiming Jiao
- The School of Medicine, Chongqing University, Chongqing, China.,Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Nie Tan
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chengyu Zhu
- The School of Medicine, Chongqing University, Chongqing, China.,Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yong Fu
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Kun Zhang
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Ding
- Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wenyue Xu
- The School of Medicine, Chongqing University, Chongqing, China.,Department of Pathogenic Biology, Army Medical University (Third Military Medical University), Chongqing, China
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10
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Denicolò S, Nair V, Leierer J, Rudnicki M, Kretzler M, Mayer G, Ju W, Perco P. Assessment of Fibrinogen-like 2 (FGL2) in Human Chronic Kidney Disease through Transcriptomics Data Analysis. Biomolecules 2022; 13:89. [PMID: 36671474 PMCID: PMC9855364 DOI: 10.3390/biom13010089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Fibrinogen-like 2 (FGL2) was recently found to be associated with fibrosis in a mouse model of kidney damage and was proposed as a potential therapeutic target in chronic kidney disease (CKD). We assessed the association of renal FGL2 mRNA expression with the disease outcome in two independent CKD cohorts (NEPTUNE and Innsbruck CKD cohort) using Kaplan Meier survival analysis. The regulation of FGL2 in kidney biopsies of CKD patients as compared to healthy controls was further assessed in 13 human CKD transcriptomics datasets. The FGL2 protein expression in human renal tissue sections was determined via immunohistochemistry. The regulators of FGL2 mRNA expression in renal tissue were identified in the co-expression and upstream regulator analysis of FGL2-positive renal cells via the use of single-cell RNA sequencing data from the kidney precision medicine project (KPMP). Higher renal FGL2 mRNA expression was positively associated with kidney fibrosis and negatively associated with eGFR. Renal FGL2 mRNA expression was upregulated in CKD as compared with healthy controls and associated with CKD progression in the Innsbruck CKD cohort (p-value = 0.0036) and NEPTUNE cohort (p-value = 0.0048). The highest abundance of FGL2 protein in renal tissue was detected in the thick ascending limb of the loop of Henle and macula densa, proximal tubular cells, as well as in glomerular endothelial cells. The upstream regulator analysis identified TNF, IL1B, IFNG, NFKB1, and SP1 as factors potentially inducing FGL2-co-expressed genes, whereas factors counterbalancing FGL2-co-expressed genes included GLI1, HNF1B, or PPARGC1A. In conclusion, renal FGL2 mRNA expression is elevated in human CKD, and higher FGL2 levels are associated with fibrosis and worse outcomes.
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Affiliation(s)
- Sara Denicolò
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Viji Nair
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Johannes Leierer
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Matthias Kretzler
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Gert Mayer
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Wenjun Ju
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Paul Perco
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, 6020 Innsbruck, Austria
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11
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Yao X, Song Y, Wang Z, Bai S, Yu H, Wang Y, Guan Y. Proteinase-activated receptor-1 antagonist attenuates brain injury via regulation of FGL2 and TLR4 after intracerebral hemorrhage in mice. Neuroscience 2022; 490:193-205. [PMID: 35182700 DOI: 10.1016/j.neuroscience.2022.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 11/25/2022]
Abstract
Proteinase-activated receptor-1 (PAR1) antagonist plays a protective effect in brain injury. We investigated the potential function and mechanisms of PAR1 antagonist in ICH-induced brain injury. Results showed that PAR1 antagonist protected against neurobehavior deficits, brain edema and BBB integrity in ICH mice via activating JNK/ERK/p38 MAPK signaling pathway at 24h after ICH. In addition, ICH resulted in the increase of FGL2 and TLR4 expression over time, and phosphorylated JNK, ERK and p38 MAPK expression. Suppression of FGL2 and TLR4 alleviated brain injury and decreased the expression of p-JNK, p-ERK, p-p38 MAPK and p-IKKα at 24 h after ICH; while overexpression of them showed the opposite result. Moreover, the protective effect of PAR1 antagonist on ICH-induced brain injury was blocked by FGL2 or TLR4 overexpression, and the levels of p-JNK, p-ERK and p-p38 MAPK were inhibited. Furthermore, PAR1 antagonist combined with TLR4 antagonist markedly alleviated brain injury after ICH at 72h. Overall, PAR1 antagonist protected against short-term brain injury, and the effect of PAR1 antagonist on ICH-induced brain injury was mediated by FGL2 or TLR4.
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Affiliation(s)
- Xiaoying Yao
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yaying Song
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ze Wang
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Shuwei Bai
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Haojun Yu
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yishu Wang
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yangtai Guan
- Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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12
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Zeng M, Li Q, Chen J, Huang W, Liu J, Wang C, Huang M, Li H, Zhou S, Xie M, Zeng K. The Fgl2 interaction with Tyrobp promotes the proliferation of cutaneous squamous cell carcinoma by regulating ERK-dependent autophagy. Int J Med Sci 2022; 19:195-204. [PMID: 34975313 PMCID: PMC8692121 DOI: 10.7150/ijms.66929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/30/2021] [Indexed: 11/05/2022] Open
Abstract
Human fibroleukin 2 (Fgl2), a member of the fibrinogen superfamily, can cleave prothrombin to generate thrombin or is secreted in a soluble form as a new type of effector of Tregs with immunomodulatory functions. However, there is little research on the role of Fgl2 in cutaneous squamous cell carcinoma (CSCC) growth. We examined the expression of Fgl2 in samples from CSCC patients and CSCC cell lines. Then, the effect of Fgl2 on CSCC was evaluated in vitro and in animals. Regulation of autophagy by Fgl2 was explored in CSCC. Coimmunoprecipitation (Co-IP) and immunofluorescence colocalization experiments were conducted to identify the regulatory effect of Fgl2 on the downstream protein Tyrobp. Then, gain- or loss-of-function analyses and evaluation of Tyrobp expression were performed to validate its role in autophagy and proliferation promoted by Fgl2. Here, our study demonstrated that Fgl2 promoted the proliferation of CSCC cells in vitro and in vivo. Knocking down Fgl2 reduced CSCC cell proliferation and inhibited autophagy in CSCC. Mechanistically, Fgl2 interacted with Tyrobp and promoted ERK-dependent autophagy, resulting in the proliferation of CSCC cells. Our study suggested that Fgl2 could be a promising prognostic biomarker and useful therapeutic target for CSCC.
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Affiliation(s)
- Mei Zeng
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China.,Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People's Republic of China
| | - Qingxiang Li
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Junzhao Chen
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Wenfu Huang
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Jinhua Liu
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Cuiyan Wang
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Manni Huang
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Hui Li
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Shu Zhou
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Miaoying Xie
- Department of Dermatology, Huizhou Municipal Central Hospital, Huizhou 516000, Guangdong, People's Republic of China
| | - Kang Zeng
- Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, People's Republic of China
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13
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Fan C, Chen H, Liu K, Wang Z. Fibrinogen-like protein 2 contributes to normal murine cardiomyocyte maturation and heart development. Exp Physiol 2021; 106:1559-1571. [PMID: 33998085 DOI: 10.1113/ep089450] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/07/2021] [Indexed: 11/08/2022]
Abstract
NEW FINDINGS What is the central question of this study? What is the role of fibrinogen-like protein 2 (FGL2) in murine cardiomyocyte maturation? What is the main finding and its importance? This is the first study showing both global Fgl2 knockout and cardiac-specific FGL2 deletion trigger early death and dilated cardiomyopathy. By using an adeno-associated virus (AAV)-mediated CRISPR/Cas9-based somatic mutagenesis system, it was demonstrated that cardiac-specific FGL2 depletion induces ventricular dilatation and remodelling, and disrupts the normal hypertrophic growth and polyploidization of cardiomyocytes. In addition, it was shown that modulation of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1 and 2 and fibroblast growth factor 2 signalling is associated with loss-of-FGL2-mediated cardiac dysfunction. These results suggest FGL2 is an important determinant of cardiomyocyte maturation. ABSTRACT In the first few weeks after birth in altricial mammals, postnatal cardiomyocytes (CMs) undergo dramatic changes, including cell volume enlargement, cell cycle withdrawal and polyploidization to become mature CMs. Aberrations in this process could disrupt the essential contractility and synchronization of adult CMs, leading to various heart diseases. However, the mechanism of CM maturation is poorly understood. Fibrinogen-like protein 2 (FGL2) is an immune coagulant which participates in maturation of multiple cell types. However, little evidence exists regarding a role of FGL2 in CM maturation. In this study, we observed that global Fgl2-/- pups had high lethality and suffered from cardiac dysfunction before P28. To further confirm the phenotype and study the mechanisms upon FGL2 deficiency, we used an adeno-associated virus (AAV)-mediated CRISPR/Cas9-based somatic mutagenesis system to generate loss-of-function mutations of Fgl2 specifically in CMs. We designed two guide RNAs (gRNAs) exclusively targeting Fgl2 exon1 and produced Fgl2-gRNA AAV9 to deliver to neonatal Cas9 mice. Here, we demonstrated the efficient FGL2 depletion in the heart after Fgl2-gRNA AAV9 delivery. Consistent with the findings in global Fgl2-/- mice, we observed AAV9-mediated FGL2 depletion triggered early death and dilated cardiomyopathy. In addition, FGL2 depletion perturbed the normal hypertrophic growth and polyploidization of maturing CMs. Furthermore, we found modulation of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1 and 2 and fibroblast growth factor 2 signalling was associated with FGL2 deficiency-mediated cardiac dysfunction. Here, we demonstrate the successful depletion of FGL2 in maturing CMs in vivo and show FGL2 is an important determinant for normal CM maturation.
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Affiliation(s)
- Cheng Fan
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hong Chen
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kun Liu
- Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhaohui Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
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14
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Yu J, Li J, Shen J, Du F, Wu X, Li M, Chen Y, Cho CH, Li X, Xiao Z, Zhao Y. The role of Fibrinogen-like proteins in Cancer. Int J Biol Sci 2021; 17:1079-1087. [PMID: 33867830 PMCID: PMC8040309 DOI: 10.7150/ijbs.56748] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
Fibrinogen-associated protein (FREP) family is a family of proteins with a fibrin domain at the carboxyl terminus. Recent investigations illustrated that two members of FREP family, fibrinogen-like protein-1 (FGL1) and fibrinogen-like protein-2 (FGL2), play crucial roles in cancer by regulating the proliferation, invasion, and migration of tumor cells, or regulating the functions of immune cells in tumor microenvironment. Meanwhile, they are potential targets for medical intervention of tumor development. In this review, we discussed the structure, and the roles of FGL1 and FGL2 in tumors, especially the roles in regulating immune cell functions.
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Affiliation(s)
- Jing Yu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China.,Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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15
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Nagdas SK, Wallace S, Eaford D, Baker R, Carr K, Raychoudhuri SS. Fibrinogen-related protein, FGL2, of hamster cauda epididymal fluid: Purification, kinetic analysis of its prothrombinase activity, and its role in segregation of nonviable spermatozoa. Mol Reprod Dev 2020; 87:1206-1218. [PMID: 33216420 DOI: 10.1002/mrd.23438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/30/2020] [Accepted: 11/02/2020] [Indexed: 11/11/2022]
Abstract
Although the epididymal environment promotes the maturation and survival of spermatozoa, not all spermatozoa remain viable during passage through the epididymis. Does the epididymis has a protective mechanism(s) to segregate the viable sperm from defective spermatozoa? Previously, we identified 260/280 kDa oligomers (termed eFGL-Epididymal Fibrinogen-Like oligomer) are composed of two disulfide-linked subunits: a 64 kDa polypeptide identified as fibrinogen-like protein-2 (FGL2) and a 33 kDa polypeptide identified as fibrinogen-like protein-1 (FGL1). Our morphological studies demonstrated that the eFGL, secreted from the principal cells of the cauda epididymis, is polymerized into a death cocoon-like complex (DCF), masking defective luminal spermatozoa but, not the viable sperm population. In the present study, we purified FGL2 from hamster cauda epididymal fluid toward homogeneity and its prothrombinase catalytic activity was examined. Time-course conversion studies revealed that all prothrombin was converted to thrombin by purified hamster FGL2. Our biochemical studies demonstrate that FGL2 is a lipid-activated serine protease and functions as a lectin by binding specific carbohydrate residues. Co-immunoprecipitation analysis demonstrated that FGL2 of cauda epididymal fluid is ubiquitinated but not the FGL1. We propose that FGL2/FGL1 oligomers represent a novel and unique mechanism to shield the viable sperm population from degenerating spermatozoa contained within the tubule lumen.
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Affiliation(s)
- Subir K Nagdas
- Department of Chemistry, Physics & Materials Science, Fayetteville State University, Fayetteville, North Carolina, USA
| | - Shamar Wallace
- Department of Chemistry, Physics & Materials Science, Fayetteville State University, Fayetteville, North Carolina, USA
| | - Don Eaford
- Department of Chemistry, Physics & Materials Science, Fayetteville State University, Fayetteville, North Carolina, USA
| | - Rashad Baker
- Department of Chemistry, Physics & Materials Science, Fayetteville State University, Fayetteville, North Carolina, USA
| | - Ky'ara Carr
- Department of Chemistry, Physics & Materials Science, Fayetteville State University, Fayetteville, North Carolina, USA
| | - Samir S Raychoudhuri
- Department of Biology, Chemistry and Environmental Health Science, Benedict College, Columbia, South Carolina, USA
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16
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Liu BQ, Bao ZY, Zhu JY, Liu H. Fibrinogen-like protein 2 promotes the accumulation of myeloid-derived suppressor cells in the hepatocellular carcinoma tumor microenvironment. Oncol Lett 2020; 21:47. [PMID: 33281958 PMCID: PMC7709556 DOI: 10.3892/ol.2020.12308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/19/2020] [Indexed: 12/19/2022] Open
Abstract
The tumor microenvironment in hepatocellular carcinoma can be classified into cellular and non-cellular components. Myeloid-derived suppressor cells (MDSCs) are cellular components of this microenvironment that serve an important role in the progression of hepatocellular carcinoma. Fibrinogen-like protein 2 (FGL2) has been demonstrated to promote tumor progression by regulating cellular components of the tumor microenvironment in various types of malignant tumor. The present study aimed to determine the expression of FGL2 in hepatocellular carcinoma and its effect on the tumor microenvironment in order to determine novel targets for liver cancer treatment. Immunohistochemistry and reverse transcription quantitative PCR were performed to determine the expression level of FGL2 and the correlation with surface markers of human MDSCs in hepatocellular carcinoma. Furthermore, a mouse hepatocellular carcinoma cell line overexpressing FGL2 was established by stable transfection of a lentivirus expressing FGL2. In addition, fresh bone marrow cells extracted from mouse femurs were in vitro cultured using conditioned medium derived from the cell line overexpressing FGL2. An orthotopic hepatocellular carcinoma mouse model was also established. The results demonstrated that FGL2 expression level in hepatocellular carcinoma tissues was closely associated with tumor size. FGL2 level was positively correlated with the expression level of the MDSC surface markers CD11b and CD33 in hepatocellular carcinoma. The in vitro results demonstrated that FGL2 could maintain the undifferentiated state of bone marrow cells, therefore promoting MDSC accumulation. Furthermore, in the orthotopic hepatocellular carcinoma mouse model, we observed that overexpression of FGL2 could promote tumor growth and significantly increase the number of MDSCs in the tumors and spleen. Taken together, these findings suggested that FGL2 may promote hepatocellular carcinoma tumor growth by promoting the accumulation of MDSCs in the tumor microenvironment.
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Affiliation(s)
- Bo-Qian Liu
- Department of Transplant and Hepatobilliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China.,Department of Anorectal Surgery, The People's Hospital of Liaoning Province, Shenyang, Liaoning 110000, P.R. China
| | - Zhi-Ye Bao
- Department of Transplant and Hepatobilliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Jia-Yi Zhu
- Department of Transplant and Hepatobilliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
| | - Hao Liu
- Department of Transplant and Hepatobilliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110000, P.R. China
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17
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Ostapchuk YO, Perfilyeva YV, Kali A, Tleulieva R, Yurikova OY, Stanbekova GE, Karalnik BV, Belyaev NN. Fc Receptor is Involved in Nk Cell Functional Anergy Induced by Miapaca2 Tumor Cell Line. Immunol Invest 2020; 51:138-153. [PMID: 32865068 DOI: 10.1080/08820139.2020.1813757] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFβ-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer. ABBREVIATIONS CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFβ-1; PI: Propidium iodide; TGFβ: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa.
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Affiliation(s)
- Yekaterina O Ostapchuk
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Yuliya V Perfilyeva
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Aikyn Kali
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan.,Biomedical Research Center, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Raikhan Tleulieva
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Oxana Yu Yurikova
- Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Gulshan E Stanbekova
- Laboratory of Protein and Nucleic Acids, M.A. Aitkhozhin's Institute of Molecular Biology and Biochemistry, Almaty, Kazakhstan
| | - Boris V Karalnik
- Scientific Center for Hygiene and Epidemiology named after Kh. Zhumatov, Natioanl Public Health Center, Almaty, Kazakhstan
| | - Nikolai N Belyaev
- Department of New Technologies, Saint-Petersburg Pasteur Institute, Saint-Petersburg, Russia
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18
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Wu S, Li M, Xu F, Li GQ, Han B, He XD, Li SJ, He QH, Lai XY, Zhou S, Zheng QY, Guo B, Chen J, Zhang KQ, Xu GL. Fibrinogen-like protein 2 deficiency aggravates renal fibrosis by facilitating macrophage polarization. Biomed Pharmacother 2020; 130:110468. [PMID: 32795921 DOI: 10.1016/j.biopha.2020.110468] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/20/2020] [Accepted: 06/24/2020] [Indexed: 10/23/2022] Open
Abstract
Renal fibrosis has no effective target for its prevention or reversal. Fibinogen-like protein 2 (Fgl2) is a novel prothrombinase exhibiting coagulation activity and immunomodulatory effects. Although Fgl2 is known to play a vital role in the development of liver and interstitial fibrosis, its function in renal fibrosis remains unclear. In this study, Fgl2 expression was found to be markedly increased in kidney tissues from mice with unilateral ureteral obstruction (UUO)-induced renal fibrosis and patients with chronic kidney disease. However, Fgl2 deficiency aggravated UUO-induced renal fibrosis, as evidenced by the significantly increasing collagen I, fibronectin, and α-SMA expression, extracellular matrix deposition, and profibrotic factor (TGF-β1) secretion. Administration of rmFgl2 (recombinant mouse Fgl2) significantly alleviated UUO-induced renal fibrosis in mice, suggesting that the increased fibrosis can be reversed by supplementing rmFgl2. Although there was no difference in the percentages of total macrophages between Fgl2+/+ and Fgl2-/- mice, Fgl2 deficiency remarkably facilitated M2 macrophage polarization and accelerated M1 macrophage polarization to a low degree, during UUO-induced renal fibrosis development in mice. Similar results were observed when Fgl2+/+ and Fgl2-/- mice bone marrow-derived macrophages were treated for M1 or M2 polarization. Moreover, Fgl2 deficiency significantly increased the phosphorylation of STAT6, a critical mediator of M2 polarization, in both UUO-induced fibrotic kidney tissues and bone marrow-derived M2 macrophages. In conclusion, the aggravation of renal fibrosis by Fgl2 deficiency is facilitated by the p-STAT6-dependent upregulation of macrophage polarization, especially of M2.
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Affiliation(s)
- Shun Wu
- Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China; Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Meng Li
- Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Feng Xu
- Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Gui-Qing Li
- Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Bo Han
- Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Xian-Dong He
- Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Shu-Jing Li
- Urinary Nephropathy Center, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, China
| | - Qian-Hui He
- Urinary Nephropathy Center, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, China
| | - Xin-Yue Lai
- First Clinical College, Chongqing Medical University, Chongqing 400016, China
| | - Shuo Zhou
- Queen Mary College, Nanchang University, Nanchang 330031, Jiangxi Province, China
| | - Quan-You Zheng
- Department of Nephrology, First Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Bo Guo
- Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Jian Chen
- Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China
| | - Ke-Qin Zhang
- Urinary Nephropathy Center, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400065, China.
| | - Gui-Lian Xu
- Department of Immunology, Basic Medicine College, Army Medical University (Third Military Medical University), Chongqing 400038, China.
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19
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Yang Y, Chen J, Yang J, Yi C, Yang F, Gao W, Li Z, Bai X. Predictive value of soluble fibrinogen-like protein 2 for survival in traumatic patients with sepsis. Clin Chim Acta 2020; 510:196-202. [PMID: 32679128 DOI: 10.1016/j.cca.2020.07.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/08/2020] [Accepted: 07/10/2020] [Indexed: 11/15/2022]
Abstract
BACKGROUND Despite significant advances in the diagnosis and management of sepsis and trauma over the past few decades, severe infection and injury continue to represent major public health challenges. Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. In this study, we evaluated whether soluble fibrinogen-like protein 2 (sFGL2) can serve as a biomarker to predict the development of sepsis in trauma patients. METHODS sFGL2 concentrations were determined by ELISA assays in sera of 75 trauma patients clinically classified into non-sepsis group and sepsis group. For comparison, 15 age- and sex-matched healthy individuals were included. RESULTS sFGL2 concentrations were dramatically elevated in trauma patients compared to healthy controls. In the patient group, the patients with sepsis showed a significant increase in sFGL2 concentrations compared with non-septic patients. Moreover, non-survivors of septic patients displayed higher sFGL2 concentrations compared with survivors. In addition, sFGL2 concentrations were positively correlated with Sequential Organ Failure Assessment (SOFA) scores, serum IL-8 and IL-10 concentrations, but reversely correlated with Glasgow coma scale (GCS) scores, platelet and lymphocyte counts. Furthermore, sFGL2 was found to be an independent predictor of 28-day mortality in traumatic patients with sepsis by logistic regression analysis. CONCLUSION sFGL2 concentrations were significantly correlated with the development and mortality of sepsis in traumatic patients. Thus, sFGL2 may serve as a potential indicator for traumatic patients with sepsis.
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Affiliation(s)
- Yang Yang
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajun Chen
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiashen Yang
- Second Clinical College, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengla Yi
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Yang
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Gao
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhanfei Li
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China.
| | - Xiangjun Bai
- Department of Emergency and Traumatic Surgery, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, China.
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20
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Leon K, Hennebold JD, Fei SS, Young KA. Transcriptome analysis during photostimulated recrudescence reveals distinct patterns of gene regulation in Siberian hamster ovaries†. Biol Reprod 2020; 102:539-559. [PMID: 31724051 PMCID: PMC7068109 DOI: 10.1093/biolre/ioz210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/13/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
In Siberian hamsters, exposure to short days (SDs, 8 h light:16 h dark) reduces reproductive function centrally by decreasing gonadotropin secretion, whereas subsequent transfer of photoinhibited hamsters to stimulatory long days (LDs, 16 L:8 D) promotes follicle stimulating hormone (FSH) release inducing ovarian recrudescence. Although differences between SD and LD ovaries have been investigated, a systematic investigation of the ovarian transcriptome across photoperiod groups to identify potentially novel factors that contribute to photostimulated restoration of ovarian function had not been conducted. Hamsters were assigned to one of four photoperiod groups: LD to maintain ovarian cyclicity, SD to induce ovarian regression, or post transfer (PT), where females housed in SD for 14-weeks were transferred to LD for 2-days or 1-week to reflect photostimulated ovaries prior to (PTd2) and following (PTw1) the return of systemic FSH. Ovarian RNA was extracted to create RNA-sequencing libraries and short-read sequencing Illumina assays that mapped and quantified the ovarian transcriptomes (n = 4/group). Ovarian and uterine masses, plasma FSH, and numbers of antral follicles and corpora lutea decreased in SD as compared to LD ovaries (P < 0.05). When reads were aligned to the mouse genome, 18 548 genes were sufficiently quantified. Most of the differentially expressed genes noted between functional LD ovaries and regressed SD ovaries; however, five main expression patterns were identified across photoperiod groups. These results, generally corroborated by select protein immunostaining, provide a map of photoregulated ovary function and identify novel genes that may contribute to the photostimulated resumption of ovarian activity.
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Affiliation(s)
- Kathleen Leon
- Department of Biological Sciences, California State University Long Beach, Long Beach, California, USA
| | - Jon D Hennebold
- Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon, USA
- Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, USA
| | - Suzanne S Fei
- Bioinformatics and Biostatistics Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, USA
| | - Kelly A Young
- Department of Biological Sciences, California State University Long Beach, Long Beach, California, USA
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21
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Fan C, Wang J, Mao C, Li W, Liu K, Wang Z. The FGL2 prothrombinase contributes to the pathological process of experimental pulmonary hypertension. J Appl Physiol (1985) 2019; 127:1677-1687. [PMID: 31580221 DOI: 10.1152/japplphysiol.00396.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fibrinogen-like protein 2 (FGL2) prothrombinase is an immune coagulant that can cleave prothrombin to thrombin, which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. FGL2 prothrombinase is mainly expressed in endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-induced rat and hypoxia-induced mouse PH models. Fgl2−/− mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling, and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of FGL2 in PH. We show FGL2 is upregulated in pulmonary vascular endothelium in human IPAH and in two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling, and reduced endothelial dysfunction. In addition, loss of FGL2 downregulated PAR1 (proteinase-activated receptor 1) expression and decreased the overactivation and consumption of platelets in hypoxia-induced PH. These results indicate FGL2 participate in the development of PH and loss of FGL2 could attenuate PH by reducing in situ thrombosis and suppressing PAR1 signaling. Thus we provide evidence that suggests FGL2 prothrombinase presents a potential therapeutic target for clinical treatment of PH. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.
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Affiliation(s)
- Cheng Fan
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jue Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaoqin Mao
- Department of Rehabilitation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenzhu Li
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kun Liu
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaohui Wang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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22
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Xu WB, Hu QH, Wu CN, Fan ZK, Song ZF. Serum soluble fibrinogen-like protein 2 concentration predicts delirium after acute pancreatitis. Brain Behav 2019; 9:e01261. [PMID: 30884164 PMCID: PMC6456778 DOI: 10.1002/brb3.1261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/20/2019] [Accepted: 02/23/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Inflammation can cause delirium. Soluble fibrinogen-like protein 2 (sFGL2) is a modulator of the immune response and more recently found to be a biomarker for brain injury. This study was designed to discover the predictive capability of serum sFGL2 concentrations for delirium after acute pancreatitis (AP). MATERIALS AND METHODS In this prospective, observational study, serum sFGL2 concentrations were quantified in 184 healthy controls and in 184 AP patients. Disease severity was assessed by Acute Physiology and Chronic Health Care Evaluation II score, Ranson score, multiple organ dysfunction score, and sequential organ failure assessment score. Delirium was recorded during hospital stay. Predictors of delirium were identified using multivariate analysis. RESULTS Serum sFGL2 concentrations were substantially higher in AP patients than in controls. Serum sFGL2 concentrations were intimately correlated with the preceding severity parameters. Serum sFGL2 and the aforementioned severity parameters were independent predictors for delirium. Under receiver operating characteristic curve, the discriminatory ability of serum sFGL2 was equivalent to those of the above-mentioned severity parameters. Moreover, serum sFGL2 dramatically improved the predictive value of the aforementioned severity parameters. CONCLUSIONS Elevation of serum sFGL2 concentrations is strongly associated with the AP severity and has the potential to distinguish delirium after AP.
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Affiliation(s)
- Wen-Bin Xu
- Department of General Surgery, The Zhejiang Xiaoshan Hospital, Hangzhou, China
| | - Qian-Hua Hu
- Department of General Surgery, The Zhejiang Xiaoshan Hospital, Hangzhou, China
| | - Chan-Ni Wu
- Department of Gastroenterology, The Zhejiang Xiaoshan Hospital, Hangzhou, China
| | - Zhi-Kun Fan
- Department of General Surgery, The Zhejiang Xiaoshan Hospital, Hangzhou, China
| | - Zhang-Fa Song
- Department of Anorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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23
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Van Tong H, Van Ba N, Hoan NX, Binh MT, Quyen DT, Son HA, Van Luong H, Quyet D, Meyer CG, Song LH, Toan NL, Velavan TP. Soluble fibrinogen-like protein 2 levels in patients with hepatitis B virus-related liver diseases. BMC Infect Dis 2018; 18:553. [PMID: 30419833 PMCID: PMC6233598 DOI: 10.1186/s12879-018-3473-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 10/31/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Clinical progression of HBV-related liver diseases is largely associated with the activity of HBV-specific T cells. Soluble fibrinogen-like protein 2 (sFGL2), mainly secreted by T cells, is an important effector molecule of the immune system. METHODS sFGL2 levels were determined by ELISA assays in sera of 296 HBV patients clinically classified into the subgroups of acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC) and patients with LC plus HCC. As control group, 158 healthy individuals were included. FGL2 mRNA was quantified by qRT-PCR in 32 pairs of tumor and adjacent non-tumor liver tissues. RESULTS sFGL2 levels were elevated in HBV patients compared to healthy controls (P < 0.0001). In the patient group, sFGL2 levels were increased in AHB compared to CHB patients (P = 0.017). sFGL2 levels were higher in LC patients compared to those without LC (P = 0.006) and were increased according to the development of cirrhosis as staged by Child-Pugh scores (P = 0.024). Similarly, HCC patients had increased sFGL2 levels compared to CHB patients (P = 0.033) and FGL2 mRNA was up-regulated in tumor tissues compared to adjacent non-tumor tissues (P = 0.043). In addition, sFGL2 levels were positively correlated with HBV-DNA loads and AST (Spearman's rho = 0.21, 0.25 and P = 0.006, 0.023, respectively), but reversely correlated with platelet counts and albumin levels (Spearman's rho = - 0.27, - 0.24 and P = 0.014, 0.033, respectively). CONCLUSIONS sFGL2 levels are induced by HBV infection and correlated with the progression and clinical outcome of HBV-related liver diseases. Thus, sFGL2 may serve as a potential indicator for HBV-related liver diseases.
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Affiliation(s)
- Hoang Van Tong
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam. .,Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam. .,Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.
| | - Nguyen Van Ba
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Mai Thanh Binh
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Dao Thanh Quyen
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Ho Anh Son
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam.,Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Hoang Van Luong
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Do Quyet
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Christian G Meyer
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam.,Medical Faculty, Duy Tan University, Da Nang, Vietnam
| | - Le Huu Song
- 108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Nguyen Linh Toan
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany. .,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam. .,Medical Faculty, Duy Tan University, Da Nang, Vietnam.
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24
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Liu XG, Liu Y, Chen F. Soluble fibrinogen like protein 2 (sFGL2), the novel effector molecule for immunoregulation. Oncotarget 2018; 8:3711-3723. [PMID: 27732962 PMCID: PMC5356913 DOI: 10.18632/oncotarget.12533] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/29/2016] [Indexed: 02/07/2023] Open
Abstract
Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen-like protein 2 belonging to the fibrinogen-related protein superfamily. It is now well characterized that sFGL2 is mainly secreted by regulatory T cell (Treg) populations, and exerts potently immunosuppressive activities. By repressing not only the differentiation and proliferation of T cells but also the maturation of dendritic cells (DCs), sFGL2 acts largely as an immunosuppressant. Moreover, sFGL2 also induces apoptosis of B cells, tubular epithelial cells (TECs), sinusoidal endothelial cells (SECs), and hepatocytes. This mini-review focuses primarily on the recent literature with respect to the signaling mechanism of sFGL2 in immunomodulation, and discusses the clinical implications of sFGL2 in transplantation, hepatitis, autoimmunity, and tumors.
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Affiliation(s)
- Xin-Guang Liu
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China
| | - Yu Liu
- School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan, P. R. China
| | - Feng Chen
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China.,Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing, China
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25
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Zuliani-Alvarez L, Marzeda AM, Deligne C, Schwenzer A, McCann FE, Marsden BD, Piccinini AM, Midwood KS. Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. Nat Commun 2017; 8:1595. [PMID: 29150600 PMCID: PMC5693923 DOI: 10.1038/s41467-017-01718-7] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 10/05/2017] [Indexed: 02/08/2023] Open
Abstract
Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs.
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Affiliation(s)
- Lorena Zuliani-Alvarez
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Anna M Marzeda
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Claire Deligne
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Anja Schwenzer
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Fiona E McCann
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK
| | - Brian D Marsden
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.,Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7DQ, UK
| | - Anna M Piccinini
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.,School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Kim S Midwood
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, UK.
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26
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Zhu Y, Zhang L, Zha H, Yang F, Hu C, Chen L, Guo B, Zhu B. Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer. Int J Biol Sci 2017; 13:804-814. [PMID: 28656005 PMCID: PMC5485635 DOI: 10.7150/ijbs.19398] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/10/2017] [Indexed: 12/16/2022] Open
Abstract
Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2-knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer.
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Affiliation(s)
- Ying Zhu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.,Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China
| | - Longhui Zhang
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.,Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China
| | - Haoran Zha
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.,Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China
| | - Fei Yang
- Department of Pathogenic Biology, Third Military Medical University, Chongqing, 400038, P. R. China
| | - Chunyan Hu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.,Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China
| | - Lin Chen
- Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400042, P. R. China
| | - Bo Guo
- Department of Pathogenic Biology, Third Military Medical University, Chongqing, 400038, P. R. China
| | - Bo Zhu
- Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China.,Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China
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27
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Nagdas SK, Winfrey VP, Olson GE. Two fibrinogen-like proteins, FGL1 and FGL2 are disulfide-linked subunits of oligomers that specifically bind nonviable spermatozoa. Int J Biochem Cell Biol 2016; 80:163-172. [PMID: 27732889 DOI: 10.1016/j.biocel.2016.10.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 10/08/2016] [Indexed: 11/16/2022]
Abstract
Nevertheless, a nonviable sperm population is present in the cauda epididymidis of many species. Degenerating spermatozoa release enzymes that could have detrimental effects on the viability of neighboring cells, and they are source of autoantigens that induce an autoimmune response if they escape the blood-epididymis barrier. Does the epididymis have specialized protective mechanism(s) to segregate the viable sperm population from defective spermatozoa? Previously, we identified a fibrinogen-like protein-2 (fgl2) that specifically binds to and polymerizes into a cocoon-like complex coating defective spermatozoa and sperm fragments. The objective of the present study is to identify the subunit composition of the fgl2-containing oligomers both in the soluble and cocoon-like complex. Our proteomic studies indicate that the 260/280kDa oligomers (termed eFGL) contain two distinct disulfide-linked subunits; 64kDa fgl2 and 33kDa fgl1. Utilizing a PCR-based cloning strategy, the 33kDa polypeptide has been identified as fibrinogen-like protein-1 (fgl1). Immunocytochemical studies revealed that fgl1 selectively binds to defective spermatozoa in the cauda epididymidis. Northern blot analysis and in situ hybridization demonstrated the high expression of fgl1 in the principal cells of the proximal cauda epididymidis. Co-immunoprecipitation analyses of cauda epididymal fluid, using anti-fgl2, demonstrate that both fgl1 and fgl2 are present in the soluble eFGL. Our study is the first to show an association of fgl1 and fgl2 both in the soluble and in the sperm-associated eFGL. We conclude that our results provide new insights into the mechanisms by which the potentially unique epididymal protein functions in the recognition and elimination of defective spermatozoa.
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Affiliation(s)
- Subir K Nagdas
- Department of Chemistry and Physics, Fayetteville State University, Fayetteville, NC, 28301, United States; Department of Cell Biology, Vanderbilt University, Nashville, TN, United States.
| | - Virginia P Winfrey
- Department of Cell Biology, Vanderbilt University, Nashville, TN, United States
| | - Gary E Olson
- Department of Cell Biology, Vanderbilt University, Nashville, TN, United States
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28
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Cloning and Tissue expression of the Tissue Prothrombinase Fgl-2 in the Sprague-Dawley Rat. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/s1071-55760200252-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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29
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Bartczak A, Chruscinski A, Mendicino M, Liu H, Zhang J, He W, Amir AZ, Nguyen A, Khattar R, Sadozai H, Lobe CG, Adeyi O, Phillips MJ, Zhang L, Gorczynski RM, Grant D, Levy GA. Overexpression of Fibrinogen-Like Protein 2 Promotes Tolerance in a Fully Mismatched Murine Model of Heart Transplantation. Am J Transplant 2016; 16:1739-50. [PMID: 26718313 DOI: 10.1111/ajt.13696] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 12/15/2015] [Accepted: 12/27/2015] [Indexed: 01/25/2023]
Abstract
Fibrinogen-like protein 2 (FGL2) is an immunomodulatory protein that is expressed by regulatory T cells (Tregs). The objective of this study was to determine if recombinant FGL2 (rFGL2) treatment or constitutive FGL2 overexpression could promote transplant tolerance in mice. Although rFGL2 treatment prevented rejection of fully mismatched cardiac allografts, all grafts were rejected after stopping treatment. Next, we generated FGL2 transgenic mice (fgl2(Tg) ) that ubiquitously overexpressed FGL2. These mice developed normally and had no evidence of the autoimmune glomerulonephritis seen in fgl2(-/-) mice. Immune characterization showed fgl2(Tg) T cells were hypoproliferative to stimulation with alloantigens or anti-CD3 and anti-CD28 stimulation, and fgl2(Tg) Tregs had increased immunosuppressive activity compared with fgl2(+/+) Tregs. To determine if FGL2 overexpression can promote tolerance, we transplanted fully mismatched cardiac allografts into fgl2(Tg) recipients. Fifty percent of cardiac grafts were accepted indefinitely in fgl2(Tg) recipients without any immunosuppression. Tolerant fgl2(Tg) grafts had increased numbers and proportions of Tregs and tolerant fgl2(Tg) mice had reduced proliferation to donor but not third party antigens. These data show that tolerance in fgl2(Tg) recipients involves changes in Treg and T cell activity that contribute to a higher intragraft Treg-to-T cell ratio and acceptance of fully mismatched allografts.
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Affiliation(s)
- A Bartczak
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.,Institute of Medial Science, University of Toronto, Toronto, Ontario, Canada
| | - A Chruscinski
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - H Liu
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.,Department of General Surgery and Organ Transplantation, First Hospital, China Medical University, Shen Yang, Liao Ning, China
| | - J Zhang
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - W He
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - A Z Amir
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.,The GI, Hepatology and Nutrition Division, the Hospital for Sick Children, Toronto, Ontario, Canada
| | - A Nguyen
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - R Khattar
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - H Sadozai
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - C G Lobe
- Cancer Research Division, Sunnybrook Health Science Centre and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - O Adeyi
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - M J Phillips
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - L Zhang
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - R M Gorczynski
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - D Grant
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - G A Levy
- Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Cheng J, Chen Y, Xu B, Wu J, He F. Association of Soluble Fibrinogen-like Protein 2 with the Severity of Coronary Artery Disease. Intern Med 2016; 55:2343-50. [PMID: 27580532 DOI: 10.2169/internalmedicine.55.6149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective The purpose of this study was to investigate the relationship between circulating soluble fibrinogen-like protein 2 (sFGL2) concentrations and the severity of coronary artery disease (CAD) in patients who underwent first-time angiography for suspected CAD. Methods Serum sFGL2 concentrations were measured in 102 consecutive patients by an enzyme-linked immunosorbent assay (ELISA). The number of circulating CD4(+)CD25(+)CD127(low) T regulatory cells (Tregs) was determined by flow cytometry and effecter cytokines, including transforming growth factor-β1 and interleukin-10 (IL-10), were also evaluated by an ELISA. Associations between sFGL2 and Tregs with angiographic indexes of the severity of CAD (i.e., number of diseased vessels and the modified Gensini score) were estimated. Results The sFGL2 levels in patients with angiographically confirmed CAD were significantly lower than those in patients with normal coronary arteries (26.95±8.53 vs. 9.88±5.46 ng/mL, p<0.001). Significant correlations were observed between the serum sFGL2 level and number of diseased vessels (r=-0.860, p<0.001) and modified Gensini score (r=-0.833, p<0.001). Using a multivariate analysis, the serum sFGL2 level was independently associated with the presence and severity of CAD. Conclusion The serum sFGL2 levels are significantly lower in the presence of CAD and correlate with the severity of the disease. Further clinical studies are needed to confirm the use of sFGL2 as a biomarker for the detection and extent of CAD.
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Affiliation(s)
- Jing Cheng
- School of Nursing, Anhui University of Traditional Chinese Medicine, China
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Long R, You Y, Li W, Jin N, Huang S, Li T, Liu K, Wang Z. Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2. Life Sci 2015; 142:8-18. [PMID: 26482204 DOI: 10.1016/j.lfs.2015.10.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 10/03/2015] [Accepted: 10/15/2015] [Indexed: 02/06/2023]
Abstract
AIMS The effects of sodium tanshinone IIA sulfonate (STS) on coronary no-reflow (CNR) relevant to microvascular obstruction (MVO) remain unknown. Studies had shown that fibrinogen-like protein 2 (FGL2) expressed in microvascular endothelial cells (MECs) is a key mediator in MVO. Thus, we aimed to elucidate the roles of STS in CNR and relations between STS and FGL2. MAIN METHODS Myocardial ischemia/reperfusion was selected to represent CNR model. The no-reflow zone and infarct area were assessed using Thioflavin S and TTC staining, and cardiac functional parameters were detected using echocardiography. Western blot was used to detected FGL2 level, fibrin level, protease-activated receptor-1 (PAR-1) activation and inflammation cells infiltration. FGL2 and inflammation cells were also identified by IHC. Microthrombus was detected by Carstairs' and MSB staining. We also detected the roles of STS on FGL2 expression, thrombin generation, phospho-Akt and NF-κB levels in MECs. KEY FINDINGS Upon treatment with STS in CNR model, the no-reflow and infarct areas decreased significantly and cardiac function improved. The FGL2 expression was inhibited by STS in vivo as well as in vitro with thrombin generation inhibition. In addition, STS up-regulates Akt phosphorylation and suppressed NF-κB expression in activated MECs. Furthermore, fibrin deposition, PAR-1 activation and inflammatory response were inhibited with STS administration in CNR model. SIGNIFICANCE Our results displayed a novel pharmacological action of STS on CNR. STS is able to ameliorate CNR through inhibition of FGL2 expression mediated by Akt and NF-κB pathways as well as prevention of MVO by suppressing fibrin deposition and inflammation.
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Affiliation(s)
- Rui Long
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ya You
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenzhu Li
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nan Jin
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiyuan Huang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Li
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Liu
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhaohui Wang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Fang KF, Chen ZJ, Liu M, Wu PS, Yu DZ. Blood pH in coronary artery microthrombosis of rats. ASIAN PAC J TROP MED 2015; 8:864-9. [DOI: 10.1016/j.apjtm.2015.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 08/20/2015] [Accepted: 09/15/2015] [Indexed: 11/29/2022] Open
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Chruscinski A, Sadozai H, Rojas-Luengas V, Bartczak A, Khattar R, Selzner N, Levy GA. Role of Regulatory T Cells (Treg) and the Treg Effector Molecule Fibrinogen-like Protein 2 in Alloimmunity and Autoimmunity. Rambam Maimonides Med J 2015; 6:RMMJ.10209. [PMID: 26241231 PMCID: PMC4524397 DOI: 10.5041/rmmj.10209] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are critical to the maintenance of immune tolerance. Treg are known to utilize a number of molecular pathways to control immune responses and maintain immune homeostasis. Fibrinogen-like protein 2 (FGL2) has been identified by a number of investigators as an important immunosuppressive effector of Treg, which exerts its immunoregulatory activity by binding to inhibitory FcγRIIB receptors expressed on antigen-presenting cells including dendritic cells, endothelial cells, and B cells. More recently, it has been suggested that FGL2 accounts for the immunosuppressive activity of a highly suppressive subset of Treg that express T cell immunoreceptor with Ig and ITIM domains (TIGIT). Here we discuss the important role of Treg and FGL2 in preventing alloimmune and autoimmune disease. The FGL2-FcγRIIB pathway is also known to be utilized by viruses and tumor cells to evade immune surveillance. Moving forward, therapies based on modulation of the FGL2-FcγRIIB pathway hold promise for the treatment of a wide variety of conditions ranging from autoimmunity to cancer.
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Affiliation(s)
| | | | | | | | | | | | - Gary A. Levy
- To whom correspondence should be addressed. E-mail:
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Yan J, Kong LY, Hu J, Gabrusiewicz K, Dibra D, Xia X, Heimberger AB, Li S. FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas. J Natl Cancer Inst 2015; 107:djv137. [PMID: 25971300 DOI: 10.1093/jnci/djv137] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms. METHODS The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and FcɣRIIB-/- mice (n = 3-18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided. RESULTS In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival (P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody (P = .01). The anti-FGL2 antibody treatment reduced CD39(+) Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in FcɣRIIB-/- mice. CONCLUSIONS FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.
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Affiliation(s)
- Jun Yan
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Ling-Yuan Kong
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Jiemiao Hu
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Konrad Gabrusiewicz
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Denada Dibra
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Xueqing Xia
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Amy B Heimberger
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
| | - Shulin Li
- Department of Pediatric Research (JY, JH, DD, XX, SL) and Department of Neurosurgery (LYK, KG, ABH), The University of Texas M.D. Anderson Cancer Center, Houston, TX.
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Zuliani-Alvarez L, Midwood KS. Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing. Adv Wound Care (New Rochelle) 2015; 4:273-285. [PMID: 26005593 DOI: 10.1089/wound.2014.0599] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 10/14/2014] [Indexed: 12/23/2022] Open
Abstract
Significance: Fibrinogen-related proteins (FRePs) comprise an intriguing collection of extracellular molecules, each containing a conserved fibrinogen-like globe (FBG). This group includes the eponymous fibrinogen as well as the tenascin, angiopoietin, and ficolin families. Many of these proteins are upregulated during tissue repair and exhibit diverse roles during wound healing. Recent Advances: An increasing body of evidence highlights the specific expression of a number of FRePs following tissue injury and infection. Upon induction, each FReP uses its FBG domain to mediate quite distinct effects that contribute to different stages of tissue repair, such as driving coagulation, pathogen detection, inflammation, angiogenesis, and tissue remodeling. Critical Issues: Despite a high degree of homology among FRePs, each contains unique sequences that enable their diversification of function. Comparative analysis of the structure and function of FRePs and precise mapping of regions that interact with a variety of ligands has started to reveal the underlying molecular mechanisms by which these proteins play very different roles using their common domain. Future Directions: Fibrinogen has long been used in the clinic as a synthetic matrix serving as a scaffold or a delivery system to aid tissue repair. Novel therapeutic strategies are now emerging that harness the use of other FRePs to improve wound healing outcomes. As we learn more about the underlying mechanisms by which each FReP contributes to the repair response, specific blockade, or indeed potentiation, of their function offers real potential to enable regulation of distinct processes during pathological wound healing.
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Affiliation(s)
- Lorena Zuliani-Alvarez
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
| | - Kim S. Midwood
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
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Rabizadeh E, Cherny I, Lederfein D, Sherman S, Binkovsky N, Rosenblat Y, Inbal A. The cell-membrane prothrombinase, fibrinogen-like protein 2, promotes angiogenesis and tumor development. Thromb Res 2014; 136:118-24. [PMID: 25496996 DOI: 10.1016/j.thromres.2014.11.023] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 11/09/2014] [Accepted: 11/30/2014] [Indexed: 12/21/2022]
Abstract
The aim of the study was to further investigate the role of fibrinogen-like protein 2 (FGL-2), a transmembrane prothrombinase that directly cleaves prothrombin to thrombin, in angiogenesis and tumor development and the mechanism(s) underlying these processes. To study angiogenesis HUVEC clones with decreased fgl-2 mRNA were generated by specific siRNA. To study tumorigenesis SCID mice were implanted with intact (wild type) and fgl-2-silenced PC-3 clones. IFN-γ treated HUVEC expressing increased fgl-2 mRNA exhibited significant capillary sprouting that was not inhibited by hirudin, whereas fgl-2 silencing completely inhibited blood-vessel formation. Tumors (poorly differentiated carcinoma) developed in all 12 mice injected with wild type PC-3 compared with 8/12 mice injected with the fgl-2-silenced PC-3 clone. The tumors developed by fgl-2-silenced PC-3 clones were smaller and less aggressive and contained significantly fewer blood vessels (p<0.05). All tumors' sections were negative for thrombin staining, indicating that FGL-2-induced tumorigenesis was not mediated by thrombin. In fgl-2-silenced tumors there was a decrease in fgl-2 mRNA (p=0.02) and ERK1/2 phosphorylation (p<0.05) by 80% and a 20%, respectively. The mechanism underlying these processes, studied in PC-3 clones, revealed that fgl-2 silencing was associated with a 65% decrease in FGF-2 mRNA (p<0.01) and a 30% down regulation of ERK1/2 phosphorylation (p<0.05). Together, these results suggest that FGL-2 mediates angiogenesis and tumorigenesis not by thrombin-mediated mechanism but rather through FGF-2/ERK signaling pathway. FGL-2 may serve as a valuable therapeutic target in the future.
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Affiliation(s)
- Esther Rabizadeh
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1); Hematology Laboratory, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
| | - Izhack Cherny
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1).
| | - Doron Lederfein
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1).
| | - Shany Sherman
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1).
| | - Natalia Binkovsky
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1).
| | - Yevgenia Rosenblat
- Pathology Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
| | - Aida Inbal
- Hemato-Oncology Laboratory, Felsenstein Medical Research Center, Petach Tikva, Israel(1); Thrombosis and Hemostasis Unit, Hematology Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel(1).
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Hu J, Yan J, Rao G, Latha K, Overwijk WW, Heimberger AB, Li S. The Duality of Fgl2 - Secreted Immune Checkpoint Regulator Versus Membrane-Associated Procoagulant: Therapeutic Potential and Implications. Int Rev Immunol 2014; 35:325-339. [PMID: 25259408 DOI: 10.3109/08830185.2014.956360] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. The biological importance of Fgl2 is evident within viral-induced fibrin depositing inflammatory diseases and malignancies and provides a compelling rationale for Fgl2 expression to not only be considered as a disease biomarker but also as a therapeutic target. This article will provide a comprehensive review of the currently known biological properties of Fgl2 and clarifies future scientific directives.
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Affiliation(s)
- Jiemiao Hu
- a Department of Pediatrics-Research , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jun Yan
- a Department of Pediatrics-Research , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Ganesh Rao
- b Department of Neurosurgery , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Khatri Latha
- b Department of Neurosurgery , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Willem W Overwijk
- c Department of Melanoma Medical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Amy B Heimberger
- b Department of Neurosurgery , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Shulin Li
- a Department of Pediatrics-Research , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR, Jie C, Ochs MF. Two clinical phenotypes in polycythemia vera. N Engl J Med 2014; 371:808-17. [PMID: 25162887 PMCID: PMC4211877 DOI: 10.1056/nejmoa1403141] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Polycythemia vera is the ultimate phenotypic consequence of the V617F mutation in Janus kinase 2 (encoded by JAK2), but the extent to which this mutation influences the behavior of the involved CD34+ hematopoietic stem cells is unknown. METHODS We analyzed gene expression in CD34+ peripheral-blood cells from 19 patients with polycythemia vera, using oligonucleotide microarray technology after correcting for potential confounding by sex, since the phenotypic features of the disease differ between men and women. RESULTS Men with polycythemia vera had twice as many up-regulated or down-regulated genes as women with polycythemia vera, in a comparison of gene expression in the patients and in healthy persons of the same sex, but there were 102 genes with differential regulation that was concordant in men and women. When these genes were used for class discovery by means of unsupervised hierarchical clustering, the 19 patients could be divided into two groups that did not differ significantly with respect to age, neutrophil JAK2 V617F allele burden, white-cell count, platelet count, or clonal dominance. However, they did differ significantly with respect to disease duration; hemoglobin level; frequency of thromboembolic events, palpable splenomegaly, and splenectomy; chemotherapy exposure; leukemic transformation; and survival. The unsupervised clustering was confirmed by a supervised approach with the use of a top-scoring-pair classifier that segregated the 19 patients into the same two phenotypic groups with 100% accuracy. CONCLUSIONS Removing sex as a potential confounder, we identified an accurate molecular method for classifying patients with polycythemia vera according to disease behavior, independently of their JAK2 V617F allele burden, and identified previously unrecognized molecular pathways in polycythemia vera outside the canonical JAK2 pathway that may be amenable to targeted therapy. (Funded by the Department of Defense and the National Institutes of Health.).
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Affiliation(s)
- Jerry L Spivak
- From the Division of Hematology, Department of Medicine (J.L.S., D.M.W., O.R., A.R.M.), Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center (M.C.), and the Basic Science Institute (C.C.T.), Johns Hopkins University School of Medicine, Baltimore; the Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago (C.J.); and the Department of Mathematics and Statistics, College of New Jersey, Ewing (M.F.O.)
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The role of soluble fibrinogen-like protein 2 in transplantation: protection or damage. Transplantation 2014; 97:1201-6. [PMID: 24717224 DOI: 10.1097/tp.0000000000000116] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen like protein 2. As a novel immunoregulatory molecule, sFGL2 is secreted mainly by T cells, especially regulatory T cells, and exerts an immunoregulatory property rather than a prothrombinase function in the immune system. sFGL2 changes not only the proliferation and differentiation of T cells but also the maturation of antigen presenting cells. Besides its innate and adaptive immunoregulatory functions, sFGL2 also induces apoptosis in cells including renal tubular epithelial cells through Fcγ receptors (FcγRs). It may affect transplantation via regulation of immunity and induction of apoptosis of different cells in a spatiotemporal manner. Here, we review the research progresses on sFGL2 including its structure, functions, and molecular mechanisms via which sFGL2 might affect organ transplantation, as well as discuss its characteristics and potential of becoming a therapeutic target in patients with rejection.
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Li WZ, Wang J, Long R, Su GH, Bukhory DK, Dai J, Jin N, Huang SY, Jia P, Li T, Fan C, Liu K, Wang Z. Novel antibody against a glutamic acid-rich human fibrinogen-like protein 2-derived peptide near Ser91 inhibits hfgl2 prothrombinase activity. PLoS One 2014; 9:e94551. [PMID: 24728278 PMCID: PMC3984148 DOI: 10.1371/journal.pone.0094551] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 03/17/2014] [Indexed: 12/11/2022] Open
Abstract
Fibrinogen-like protein 2 (fgl2) is highly expressed in microvascular endothelial cells in diseases associated with microcirculatory disturbances and plays a crucial role in microthrombosis. Previous studies have demonstrated that the Ser89 residue is a critical site for mouse fgl2 prothrombinase activity. The aim of this study was to investigate the prothrombinase inhibitory ability of antibodies against an hfgl2-derived peptide. The peptide was termed NPG-12 because it is located at the N-terminus of membrane-bound hfgl2, contains 12 amino acid residues (corresponding to residues 76 to 87), and is rich in Glu. This peptide was selected as an antigenic determinant to produce antibodies in immunized rabbits using the DNAStar and HomoloGene software program. Abundant hfgl2 expression was induced in human umbilical vein endothelial cells through treatment with TNF-α. The generated anti-NPG-12 antibodies specifically recognize fgl2, as determined by ELISA, Western Blot and immunostaining. Moreover, one-stage clotting and thrombin generation tests provide evidence that the antibodies can reduce the hfgl2 prothrombinase activity without affecting the platelet-poor plasma prothrombin time (PT) or the activated partial thromboplastin time (APTT). In addition, the antibodies exerted undetectable influence on the proliferation or activation of bulk T cell populations. In conclusion, the selected peptide sequence NPG-12 may be a critical domain for hfgl2 prothrombinase activity, and the development of inhibitors against this sequence may be promising for research or management of hfgl2-associated microcirculatory disturbances.
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Affiliation(s)
- Wen-Zhu Li
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jue Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Long
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guan-Hua Su
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dinesh-Kumar Bukhory
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Dai
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nan Jin
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shi-Yuan Huang
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Jia
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Li
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Fan
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Liu
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaohui Wang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Zhao Z, Yang C, Li L, Zhao T, Wang L, Rong R, Yang B, Xu M, Zhu T. Increased peripheral and local soluble FGL2 in the recovery of renal ischemia reperfusion injury in a porcine kidney auto-transplantation model. J Transl Med 2014; 12:53. [PMID: 24559374 PMCID: PMC3936847 DOI: 10.1186/1479-5876-12-53] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 02/19/2014] [Indexed: 01/08/2023] Open
Abstract
Background Regulatory T cells (Treg) protect kidney against ischemia reperfusion (IR) injury via suppressing innate immunity, but the mechanism has not been fully clarified. Soluble fibrinogen-like protein 2 (sFGL2), a novel effector of Treg, may affect apoptosis and inflammation. This study investigated the role of sFGL2 in renal IR injury in a porcine kidney auto-transplantation model. Materials and methods The left kidney was retrieved from mini pigs and infused by University of Wisconsin solution into the renal artery with the renal artery and vein clamped for 24-h cold storage. After the right nephrectomy, the left kidney was auto-transplanted into the right for 2 weeks. 3 pigs were sacrificed at day 2, 5, 7, 10 and 14 post-transplantation respectively. Collected renal tissues and daily blood samples were stored for further analyses. Results Both serum creatinine and blood urea nitrogen were maximized during day 2 to 5 and followed by a gradual recovery over 2 weeks. The similar pattern were showed in histological damage, myeloperoxidase + cells and apoptosis in the kidney, as well as circulating TNF-α and IFN-γ. Serum sFGL2 presented a fluctuating increase and reached a peak at day 10. The expression of sFGL2 and its receptor FcγRIIB as well as Foxp3 and IL-10 in the kidney was notably increased from day 5 to 10. Conclusion The increased sFGL2 together with FcγRIIB during renal recovery after IR injury suggested that sFGL2 might be a potential renoprotective mediator involved in the renal self-repairing and remodeling in this 2-week porcine auto-transplantation model.
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Affiliation(s)
| | | | | | | | | | | | - Bin Yang
- Department of Urology, Zhongshan Hospital, Fudan University; Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai 200032, China.
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Balakrishnan L, Bhattacharjee M, Ahmad S, Nirujogi RS, Renuse S, Subbannayya Y, Marimuthu A, Srikanth SM, Raju R, Dhillon M, Kaur N, Jois R, Vasudev V, Ramachandra Y, Sahasrabuddhe NA, Prasad TK, Mohan S, Gowda H, Shankar S, Pandey A. Differential proteomic analysis of synovial fluid from rheumatoid arthritis and osteoarthritis patients. Clin Proteomics 2014; 11:1. [PMID: 24393543 PMCID: PMC3918105 DOI: 10.1186/1559-0275-11-1] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Accepted: 12/10/2013] [Indexed: 01/09/2023] Open
Abstract
Background Rheumatoid arthritis and osteoarthritis are two common musculoskeletal disorders that affect the joints. Despite high prevalence rates, etiological factors involved in these disorders remain largely unknown. Dissecting the molecular aspects of these disorders will significantly contribute to improving their diagnosis and clinical management. In order to identify proteins that are differentially expressed between these two conditions, a quantitative proteomic profiling of synovial fluid obtained from rheumatoid arthritis and osteoarthritis patients was carried out by using iTRAQ labeling followed by high resolution mass spectrometry analysis. Results We have identified 575 proteins out of which 135 proteins were found to be differentially expressed by ≥3-fold in the synovial fluid of rheumatoid arthritis and osteoarthritis patients. Proteins not previously reported to be associated with rheumatoid arthritis including, coronin-1A (CORO1A), fibrinogen like-2 (FGL2), and macrophage capping protein (CAPG) were found to be upregulated in rheumatoid arthritis. Proteins such as CD5 molecule-like protein (CD5L), soluble scavenger receptor cysteine-rich domain-containing protein (SSC5D), and TTK protein kinase (TTK) were found to be upregulated in the synovial fluid of osteoarthritis patients. We confirmed the upregulation of CAPG in rheumatoid arthritis synovial fluid by multiple reaction monitoring assay as well as by Western blot. Pathway analysis of differentially expressed proteins revealed a significant enrichment of genes involved in glycolytic pathway in rheumatoid arthritis. Conclusions We report here the largest identification of proteins from the synovial fluid of rheumatoid arthritis and osteoarthritis patients using a quantitative proteomics approach. The novel proteins identified from our study needs to be explored further for their role in the disease pathogenesis of rheumatoid arthritis and osteoarthritis. Sartaj Ahmad and Raja Sekhar Nirujogi contributed equally to this article.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Subramanian Shankar
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India.
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Yang G, Hooper WC. Physiological functions and clinical implications of fibrinogen-like 2: A review. World J Clin Infect Dis 2013; 3:37-46. [PMID: 26161303 PMCID: PMC4495006 DOI: 10.5495/wjcid.v3.i3.37] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/23/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
Fibrinogen-like 2 (FGL2) encompasses a transmembrane (mFGL2) and a soluble (sFGL2) form with differential tertiary structure and biological activities. Typically, mFGL2 functions as prothrombinase that is capable of initiating coagulation in tissue without activation of the blood clotting cascade, whereas sFGL2 largely acts as an immunosuppressor that can repress proliferation of alloreactive T lymphocytes and maturation of bone marrow dendritic cells. Protein sequences of FGL2 exhibit evolutionary conservation across wide variety of species, especially at the carboxyl terminus that contains fibrinogen related domain (FRED). The FRED of FGL2 confers specificity and complexity in the action of FGL2, including receptor recognition, calcium affiliation, and substrate binding. Constitutive expression of FGL2 during embryogenesis and in mature tissues suggests FGL2 might be physiologically important. However, excessive induction of FGL2 under certain medical conditions (e.g., pathogen invasion) could trigger complement activation, inflammatory response, cellular apoptosis, and immune dysfunctions. On the other hand, complete absence of FGL2 is also detrimental as lack of FGL2 can cause autoimmune glomerulonephritis and acute cellular rejection of xenografts. All these roles involve mFGL2, sFGL2, or their combination. Although it is not clear how mFGL2 is cleaved off its host cells and secreted into the blood, circulating sFGL2 has been found correlated with disease severity and viral loading among patients with human hepatitis B virus or hepatitis C virus infection. Further studies are warranted to understand how FGL2 expression is regulated under physiological and pathological conditions. Even more interesting is to determine whether mFGL2 can fulfill an immunoregulatory role through its FRED at carboxyl end of the molecule and, and vice versa, whether sFGL2 is procoagulant upon binding to a target cell. Knowledge in this area should shed light on development of sFGL2 as an alternative immunosuppressive agent for organ transplantation or as a biomarker for predicting disease progression, monitoring therapeutic effects, and targeting FGL2 for repression in ameliorating fulminant viral hepatitis.
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Zhao Z, Yang C, Tang Q, Zhao T, Jia Y, Ma Z, Rong R, Xu M, Zhu T. Serum level of soluble fibrinogen-like protein 2 in renal allograft recipients with acute rejection: a preliminary study. Transplant Proc 2013. [PMID: 23195010 DOI: 10.1016/j.transproceed.2012.05.082] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Soluble fibrinogen-like protein 2 (sfgl2), which is mainly secreted by T cells, is a novel effector of regulatory T cells with immunosuppressive functions. The aim of this study was to investigate serum levels of sfgl2 among renal allograft recipients. METHODS From November 2010 to August 2011 we retrospectively divided 47 renal allograft recipients into an acute rejection (n = 19) versus a stable group (n = 28) according to allograft biopsy results, using the Banff 2007 classification. The acute rejection group was subdivided into grade I (n = 8) versus grade II T-cell-mediated (n = 6) or antibody-mediated rejection episodes (n = 5). Peripheral blood samples were collected at the time of biopsy. Fourteen healthy volunteers were included as normal group controls. Serum levels of sfgl2 were analyzed by enzyme-linked immunosorbent assay. RESULTS Serum levels of sfgl2 were increased among renal allograft recipients suffering from biopsy-proven acute rejection episodes (61.91 ± 45.68 ng/mL), versus those with stable allografts (38.59 ± 19.92 ng/mL, P < .05) or healthy volunteers (29.10 ± 18.08 ng/mL, P < .05). The sfgl2 level was significantly higher among patients with antibody-mediated (118.48 ± 55.54 ng/mL) than T-cell-mediated acute rejection episodes (41.71 ± 16.44 ng/mL, P < .01). Serum sfgl2 levels were remarkably elevated in patients with grade II (51.87 ± 19.13 ng/mL) versus grade I T-cell-mediated rejection (34.10 ± 9.26 ng/mL, P < .05). CONCLUSIONS Serum sfgl2 levels were increased among renal allograft recipients with acute rejection episodes to an extent dependent upon the pathological type and severity of the response.
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Affiliation(s)
- Z Zhao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, PR China
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Zhao Z, Wang L, Yang C, Zhao T, Li L, Hu L, Wu D, Rong R, Xu M, Zhu T. Soluble FGL2 induced by tumor necrosis factor-α and interferon-γ in CD4+ T cells through MAPK pathway in human renal allograft acute rejection. J Surg Res 2013; 184:1114-22. [PMID: 23664593 DOI: 10.1016/j.jss.2013.04.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Revised: 03/27/2013] [Accepted: 04/05/2013] [Indexed: 01/22/2023]
Abstract
BACKGROUND Acute rejection (AR), initiated by alloreactive CD4(+) T cells, hampers allograft survival. Soluble fibrinogen-like protein 2 (sFGL2) is a novel effector of CD4(+) T cells. We previously found that serum sFGL2 significantly increased in renal allograft recipients with AR. In this study, sFGL2 secretion by CD4(+) T cells and its mechanism were further explored both in vivo and in vitro. MATERIALS AND METHODS Forty cases of living-related renal transplant recipients with biopsy-proven AR or stable renal function were collected and detected serum sFGL2, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and peripheral CD4(+) T cells. In vitro, the isolated human CD4(+) T cells were stimulated by TNF-α or IFN-γ. sFGL2 in the supernatant and mitogen-activated protein kinase (MAPK) proteins in the CD4(+) T cells were investigated. Approval for this study was obtained from the Ethics Committee of Fudan University. RESULTS sFGL2, TNF-α, IFN-γ, and CD4(+) T cells were significantly increased in the peripheral blood of renal allograft recipients with AR. Stimulation with 1000 U/mL TNF-α or 62.5 U/mL IFN-γ for 48 h provided an optimal condition for CD4(+) T cells to secrete sFGL2 in vitro. Phosphorylated (p-) c-Jun N-terminal kinase was remarkably upregulated in the activated CD4(+) T cells, whereas no significant changes were found in p-p38 MAPK or p-ERK1/2 expression. Furthermore, inhibition of c-Jun N-terminal kinase significantly reduced sFGL2 secretion by CD4(+) T cells. CONCLUSIONS sFGL2 secretion by CD4(+) T cells can be induced with TNF-α and IFN-γ stimulation through MAPK signaling in renal allograft AR. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection.
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Affiliation(s)
- Zitong Zhao
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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Liu Y, Xu L, Zeng Q, Wang J, Wang M, Xi D, Wang X, Yang D, Luo X, Ning Q. Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis. Liver Int 2012; 32:1585-1595. [PMID: 22925132 DOI: 10.1111/j.1478-3231.2012.02865.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 07/22/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fibrinogen-like protein 2 (FGL2), which directly generates thrombin from prothrombin without activation of the conventional coagulation cascade, was shown to be overexpressed in various human malignant tumours. AIMS Herein, we aimed to investigate its expression pattern, biological function and mechanism of action in hepatocellular carcinoma (HCC). METHODS FGL2 expression and colocalization with fibrin was examined in 15 HCC tissues. FGL2 downregulation was performed by targeting microRNA in a HCCLM6 cell line in which FGL2 was highly expressed in xenografts of nude mice. The effects of FGL2 knockdown on tumour growth and angiogenesis were evaluated in vitro and in vivo. Cytometric bead arrays were employed to identify FGL2-regulated signalling pathways. RESULTS FGL2 was overexpressed in HCC tissues and colocalized with fibrin deposition. Knockdown of FGL2 expression in HCCLM6 cells (hFGL2(low) HCCLM6) resulted in delayed xenografts tumour growth within an observation period of 42 days and decreased vascularization, which was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In vitro hFGL2(low) HCCLM6 cells exhibited decreased proliferation without significant induction of apoptosis. Overexpression of FGL2 in HCCLM6 cells or addition of recombinant hFGL2 protein induced phosphorylation of p38-MAPK and ERK1/2 involving protease-activated receptors (PARs).activation. CONCLUSIONS FGL2 contributes to HCC tumour growth and angiogenesis in a thrombin-dependent manner, and downregulation of its expression might be of therapeutic significance in HCC.
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Affiliation(s)
- Yanling Liu
- Department and Institute of Infectious Disease, Tongji hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shao L, Wu D, Zhang P, Li W, Wang J, Su G, Liao Y, Wang Z, Liu K. The Significance of Microthrombosis and fgl2 in No-Reflow Phenomenon of Rats With Acute Myocardial Ischemia/Reperfusion. Clin Appl Thromb Hemost 2012; 19:19-28. [PMID: 22387586 DOI: 10.1177/1076029612437577] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Affiliation(s)
- Liang Shao
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Daying Wu
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Ping Zhang
- Department of Neurology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Wenzhu Li
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Jue Wang
- Department of Hematology, Tongji Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Guanhua Su
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Zhaohui Wang
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
| | - Kun Liu
- Department of Cardiology, Union Hospital of Huazhong, University of Science and Technology, Wuhan, Hubei Province, China
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Rebl A, Verleih M, Korytář T, Kühn C, Wimmers K, Köllner B, Goldammer T. Identification of differentially expressed protective genes in liver of two rainbow trout strains. Vet Immunol Immunopathol 2012; 145:305-15. [DOI: 10.1016/j.vetimm.2011.11.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 11/23/2011] [Accepted: 11/28/2011] [Indexed: 12/30/2022]
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Li W, Han M, Li Y, Chen D, Luo X, Ning Q. Antiviral resistance mutations potentiate HBV surface antigen-induced transcription of hfgl2 prothrombinase gene. BIOCHEMISTRY (MOSCOW) 2011; 76:1043-50. [PMID: 22082274 DOI: 10.1134/s0006297911090094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Antiviral resistance mutations in the hepatitis B virus (HBV) polymerase (pol) gene have been demonstrated to play an important role in the progression of liver disease and the development of hepatocellular carcinoma. The HBV pol gene overlaps the S gene encoding surface antigen (HBsAg). Previous studies from our laboratory have shown that HBV core protein (HBc) and X protein (HBx), but not HBV S protein (HBs), promote hfgl2 prothrombinase transcription. To investigate whether the nucleotide (nucleoside)-induced resistant mutations of HBs potentiate transcription of hfgl2 prothrombinase gene, we generated two mutant HB expression constructs harboring rtM204V/sI195M or rtM204I/sW196L mutations. Two mutant expression plasmids were co-transfected with hfgl2 promoter luciferase-reporter plasmids and β-galactosidase plasmid in CHO cells and HepG2 cells, respectively. Luciferase assay showed that the rtM204I/V mutant HBs could activate the transcription of hfgl2 promoter compared with the wild type HBs. Site-directed mutagenesis and further experiment (co-transfection) demonstrated that transcription factor Ets translocated to its cognate cis-element in the hfgl2 promoter. The results show that mutated HBs caused by antiviral drug resistance induce transcription of the hfgl2 gene dependent on the transcription factor Ets.
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Affiliation(s)
- Weina Li
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shalev I, Selzner N, Helmy A, Foerster K, Adeyi OA, Grant DR, Levy G. The Role of FGL2 in the Pathogenesis and Treatment of Hepatitis C Virus Infection. Rambam Maimonides Med J 2010; 1:e0004. [PMID: 23908776 PMCID: PMC3721661 DOI: 10.5041/rmmj.10004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide and remains the most common indication for liver transplantation. The current standard of care leads to a sustained viral response of roughly 50% of treated patients at best. Furthermore, anti-viral therapy is expensive, prolonged, and associated with serious side-effects. Evidence suggests that a poor response to treatment may be the result of a suppressed anti-viral immunity due to the presence of increased numbers and activity of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg cells). We and others have recently identified fibrinogen-like protein 2 (FGL2) as a putative effector of Treg cells, which accounts for their suppressive function through binding to Fc gamma receptors (FcγR). In an experimental model of fulminant viral hepatitis, our laboratory showed that increased plasma levels of FGL2 pre- and post-viral infection were predictive of susceptibility and severity of disease. Moreover, treatment with antibody to FGL2 fully protected susceptible animals from the lethality of the virus, and adoptive transfer of wild-type Treg cells into resistant fgl2-deficient animals accelerated their mortality post-infection. In patients with HCV infection, plasma levels of FGL2 and expression of FGL2 in the liver correlated with the course and severity of the disease. Collectively, these studies suggest that FGL2 may be used as a biomarker to predict disease progression in HCV patients and be a logical target for the development of novel therapeutic approaches for the treatment of patients with HCV infection.
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Affiliation(s)
| | | | | | | | | | | | - Gary Levy
- To whom correspondence should be addressed. E-mail:
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