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Lu X, Zhu H, Liu M, Xu Y, Yang Z, Bai J, Jiang P, Wang X. Serum amyloid P component suppresses porcine epidemic diarrhea virus replication through TLR4-mediated IFN-β signaling pathway. Vet Microbiol 2025; 304:110459. [PMID: 40080977 DOI: 10.1016/j.vetmic.2025.110459] [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: 12/26/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Porcine epidemic diarrhea virus (PEDV) is a porcine enteropathogenic coronavirus that causes significant economic losses in many Asian and European countries. It is characterized by lethal watery diarrhea and high mortality rate in piglets. Serum amyloid P component (SAP), a member of acute response phase protein (APP) family, has been reported to play a crucial role in innate immune response against various microbial pathogens. However, its antiviral activities are little known. In this study, the antiviral activity of SAP during PEDV infection was investigated. In virus-infected IPEC cells, it was found that SAP expression was significantly upregulated. To study the role of SAP in PEDV replication, the expression of SAP was regulated in cells using eukaryotic expression plasmids expressing the SAP protein and sgRNA. PEDV replication was then assessed through real-time PCR, Western blotting, and TCID50 assays. The result showed that PEDV replication was inhibited in cells overexpressing SAP and promoted in cells with SAP knocking out. To further investigate the mechanism by which SAP inhibits PEDV replication, Interferon Beta (IFN-β) and its related signaling pathway proteins were detected. The results demonstrated that SAP activates the promoter of (IFN-β) and IFN regulatory factor 3 (IRF3) mediated by Toll-Like Receptor 4 (TLR4) signaling. During PEDV infection, SAP enhances TLR4-mediated IFN-β signaling, leading to increased IFN-β expression, which subsequently suppresses PEDV replication. By using TBK1/IKBKE inhibitor MRT67307 in PEDV-infected cells, the antiviral activity of SAP was inhibited. This suggests that the antiviral effect of SAP may rely on the activation of the TBK1/IKBKE signaling pathway, which is critical for the induction of type I interferons and other antiviral responses. Moreover, the interaction between SAP and PEDV N protein and the functional domain of SAP were investigated. From the results of this study, it can be concluded that the interaction between SAP and PEDV N protein activates the TLR4-mediated IFN signaling pathway, thereby inhibiting PEDV replication.
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Affiliation(s)
- Xinchang Lu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Huixin Zhu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Mingyu Liu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Yufan Xu
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhen Yang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
| | - Juan Bai
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co‑Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Ping Jiang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co‑Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China
| | - Xianwei Wang
- Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co‑Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
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Gürses D, Yılmaz M, Avcı E, Oğuz M, Sayın E, Yüksel S. Evaluation of Pentraxin-3 levels in children with multisystem inflammatory syndrome. Cardiol Young 2025; 35:317-323. [PMID: 39618407 DOI: 10.1017/s1047951124036175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
BACKGROUND Early recognition of cardiac involvement and prediction of disease prognosis are essential for the management of inflammatory diseases such as multisystem inflammatory syndrome. This study aimed to investigate the role of Pentraxin-3 levels in identifying cardiac involvement and evaluating disease severity in patients with multisystem inflammatory syndrome. METHODS The study included 56 multisystem inflammatory syndrome patients and 26 healthy children as a control group. The multisystem inflammatory syndrome group was divided into those with cardiac involvement (n = 34) and those without (n = 22), as well as those with clinically mild-moderate (n = 30) and severe (n = 26) multisystem inflammatory syndrome. Blood samples for measurement of Pentraxin-3 levels were obtained from all patients before treatment and from the healthy controls. RESULTS In the patient group, the mean age was 8.2 ± 4 years (range: 2-17 years), and the male-to-female ratio was 1.8. In the control group, these values were 9.5 ± 3.7 years (range: 2-16 years) and 1.9, respectively (p > 0.05). Plasma Pentraxin-3 levels were significantly higher in multisystem inflammatory syndrome patients compared to controls (7.1 ± 5 ng/mL vs. 2.9 ± 2.1 ng/mL, p = 0.001). Patients with cardiac involvement had a significantly higher median Pentraxin-3 level than those without (5.8 ng/mL vs. 4.1 ng/mL, p = 0.004). Severe disease was also associated with a higher median Pentraxin-3 level compared to mild-moderate disease (6.1 ng/mL vs. 4.4 ng/mL, p = 0.001). Pentraxin-3 level was negatively correlated with left ventricular ejection fraction and positively correlated with B-type natriuretic peptide, troponin. CONCLUSION Elevated Pentraxin-3 levels in multisystem inflammatory syndrome patients may help predict the clinical course of the disease and cardiac involvement. However, larger-scale prospective studies are needed to further elucidate this.
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Affiliation(s)
- Dolunay Gürses
- Department of Pediatric Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Münevver Yılmaz
- Department of Pediatric Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Esin Avcı
- Department of Medical Biochemistry, Faculty of Medicine, Pamukkale University Denizli, Denizli, Turkey
| | - Merve Oğuz
- Department of Pediatric Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Emine Sayın
- Department of Pediatric Cardiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Selçuk Yüksel
- Department of Pediatric Rheumatology, Faculty of Medicine, Onsekiz Mart University Çanakkale, Pamukkale, Turkey
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Jung H, Kang J, Han KM, Kim H. Prognostic Value of Pentraxin3 Protein Expression in Human Malignancies: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:3754. [PMID: 39594709 PMCID: PMC11593206 DOI: 10.3390/cancers16223754] [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: 09/11/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pentraxin 3 (PTX3), a member of the pentraxin superfamily, plays diverse roles in immunity and inflammation. Its dual role in tumorigenesis, exhibiting both protumoral and antitumoral effects, has been the subject of conflicting reports. High PTX3 expression levels in serum and tumor tissues have been associated with poor prognosis in various malignancies, suggesting its potential as a prognostic biomarker. Through this meta-analysis, we aim to comprehensively assess the prognostic significance of PTX3 protein expression in human malignancies and evaluate its potential as a pan-cancer prognostic marker. METHODS A systematic literature search was conducted across the PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library databases. Studies were included if they assessed the association between PTX3 protein expression and overall survival (OS) in cancer patients. Hazard ratios (HRs) were pooled using a random-effects model. Subgroup analyses were performed based on the method of PTX3 assessment, and publication bias was evaluated using Egger's and Begg's tests. RESULTS Nine studies encompassing 1215 patients were included in the analysis. High PTX3 expression was significantly associated with poorer OS (HR = 1.89, 95% CI = 1.55-2.32, p < 0.01) with no significant heterogeneity (I2 = 0%). Subgroup analysis revealed consistent results across different assessment methods (immunohistochemistry: HR = 1.93, p < 0.01; immunoassay: HR = 1.86, p < 0.01). However, publication bias was detected (Egger's test, p = 0.03). CONCLUSIONS High PTX3 protein expression is associated with a poor prognosis in various malignancies, supporting its potential as a prognostic biomarker.
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Affiliation(s)
| | | | | | - Hyunchul Kim
- Department of Pathology, CHA Ilsan Medical Center, Goyang-si 10414, Gyeonggi-do, Republic of Korea (J.K.); (K.-M.H.)
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Wojciuk B, Frulenko I, Brodkiewicz A, Kita D, Baluta M, Jędrzejczyk F, Budkowska M, Turkiewicz K, Proia P, Ciechanowicz A, Kostrzewa-Nowak D, Nowak R. The Complement System as a Part of Immunometabolic Post-Exercise Response in Adipose and Muscle Tissue. Int J Mol Sci 2024; 25:11608. [PMID: 39519159 PMCID: PMC11545998 DOI: 10.3390/ijms252111608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
The precise molecular processes underlying the complement's activation, which follows exposure to physical stress still remain to be fully elucidated. However, some possible mechanisms could play a role in initiating changes in the complement's activity, which are observed post-exposure to physical stress stimuli. These are mainly based on metabolic shifts that occur in the microenvironment of muscle tissue while performing its function with increased intensity, as well as the adipose tissue's role in sterile inflammation and adipokine secretion. This review aims to discuss the current opinions on the possible link between the complement activation and diet, age, sex, and health disorders with a particular emphasis on endocrinopathies and, furthermore, the type of physical activity and overall physical fitness. It has been indicated that regular physical activity incorporated into therapeutic strategies potentially improves the management of particular diseases, such as, e.g., autoimmune conditions. Moreover, it represents a favorable influence on immunoaging processes. A better understanding of the complement system's interaction with physical activity will support established clinical therapies targeting complement components.
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Affiliation(s)
- Bartosz Wojciuk
- Department of Diagnostic Immunology, Chair of Microbiology, Immunology and Laboratory Medicine, Pomeranian Medical University in Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
| | - Ignacy Frulenko
- Pomeranian Medical University in Szczecin, 1 Rybacka St., 70-204 Szczecin, Poland;
- Department of Pathology, Pomeranian Medical University in Szczecin, 1 Unii Lubelskiej St., 71-242 Szczecin, Poland
| | - Andrzej Brodkiewicz
- Department of Pediatrics, Pediatric Nephrology, Dialysis and Acute Intoxications, Pomeranian Medical University, 4 Mączna St., 70-204 Szczecin, Poland; (A.B.); (D.K.); (M.B.); (F.J.)
| | - Dagmara Kita
- Department of Pediatrics, Pediatric Nephrology, Dialysis and Acute Intoxications, Pomeranian Medical University, 4 Mączna St., 70-204 Szczecin, Poland; (A.B.); (D.K.); (M.B.); (F.J.)
| | - Monica Baluta
- Department of Pediatrics, Pediatric Nephrology, Dialysis and Acute Intoxications, Pomeranian Medical University, 4 Mączna St., 70-204 Szczecin, Poland; (A.B.); (D.K.); (M.B.); (F.J.)
| | - Filip Jędrzejczyk
- Department of Pediatrics, Pediatric Nephrology, Dialysis and Acute Intoxications, Pomeranian Medical University, 4 Mączna St., 70-204 Szczecin, Poland; (A.B.); (D.K.); (M.B.); (F.J.)
| | - Marta Budkowska
- Department of Medical Analytics, Pomeranian Medical University of Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
| | - Karolina Turkiewicz
- Department of Laboratory Diagnostics, University Clinical Hospital No. 2, Pomeranian Medical University in Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
| | - Patrizia Proia
- Sport and Exercise Sciences Research Unit, Department of Psychology, Educational Science and Human Movement, University of Palermo, 90144 Palermo, Italy;
| | - Andrzej Ciechanowicz
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
| | - Dorota Kostrzewa-Nowak
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 72 Powstańców Wlkp. Al., 70-111 Szczecin, Poland;
- Department of Biopharmaceutics and Pharmacodynamics, Faculty of Pharmacy, Medical University of Gdańsk, 107 Hallera St., 80-416 Gdańsk, Poland
| | - Robert Nowak
- Department of Pathology, Pomeranian Medical University in Szczecin, 1 Unii Lubelskiej St., 71-242 Szczecin, Poland
- Institute of Physical Culture Sciences, University of Szczecin, 17C Narutowicza St., 70-240 Szczecin, Poland
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Panebianco M, Ciccarese C, Strusi A, Beccia V, Carbone C, Agostini A, Piro G, Tortora G, Iacovelli R. The Role of the Complement in Clear Cell Renal Carcinoma (ccRCC)-What Future Prospects Are There for Its Use in Clinical Practice? Cancers (Basel) 2024; 16:490. [PMID: 38339243 PMCID: PMC10854780 DOI: 10.3390/cancers16030490] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/12/2024] [Accepted: 01/18/2024] [Indexed: 02/12/2024] Open
Abstract
In recent years, the first-line available therapeutic options for metastatic renal cell carcinoma (mRCC) have radically changed with the introduction into clinical practice of new immune checkpoint inhibitor (ICI)-based combinations. Many efforts are focusing on identifying novel prognostic and predictive markers in this setting. The complement system (CS) plays a central role in promoting the growth and progression of mRCC. In particular, mRCC has been defined as an "aggressive complement tumor", which encompasses a group of malignancies with poor prognosie and highly expressed complement components. Several preclinical and retrospective studies have demonstrated the negative prognostic role of the complement in mRCC; however, there is little evidence on its possible role as a predictor of the response to ICIs. The purpose of this review is to explore more deeply the physio-pathological role of the complement in the development of RCC and its possible future use in clinical practice as a prognostic and predictive factor.
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Affiliation(s)
- Martina Panebianco
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
| | - Chiara Ciccarese
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
| | - Alessandro Strusi
- Medical Oncology, Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.S.); (V.B.)
| | - Viria Beccia
- Medical Oncology, Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.S.); (V.B.)
| | - Carmine Carbone
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
| | - Antonio Agostini
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
| | - Geny Piro
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
| | - Giampaolo Tortora
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
- Medical Oncology, Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.S.); (V.B.)
| | - Roberto Iacovelli
- Medical Oncology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.P.); (C.C.); (C.C.); (A.A.); (G.P.); (G.T.)
- Medical Oncology, Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy; (A.S.); (V.B.)
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Ma YJ, Parente R, Zhong H, Sun Y, Garlanda C, Doni A. Complement-pentraxins synergy: Navigating the immune battlefield and beyond. Biomed Pharmacother 2023; 169:115878. [PMID: 37952357 DOI: 10.1016/j.biopha.2023.115878] [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: 08/29/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
The complement is a crucial immune defense system that triggers rapid immune responses and offers efficient protection against foreign invaders and unwanted host elements, acting as a sentinel. Activation of the complement system occurs upon the recognition of pathogenic microorganisms or altered self-cells by pattern-recognition molecules (PRMs) such as C1q, collectins, ficolins, and pentraxins. Recent accumulating evidence shows that pentraxins establish a cooperative network with different classes of effector PRMs, resulting in synergistic effects in complement activation. This review describes the complex interaction of pentraxins with the complement system and the implications of this cooperative network for effective host defense during pathogen invasion.
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Affiliation(s)
- Ying Jie Ma
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, DK-2800, Denmark.
| | | | - Hang Zhong
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Haartman Institute, University of Helsinki, Helsinki, Finland
| | - Yi Sun
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, DK-2800, Denmark
| | - Cecilia Garlanda
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Andrea Doni
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
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7
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Wang Y, Chen W, Ding S, Wang W, Wang C. Pentraxins in invertebrates and vertebrates: From structure, function and evolution to clinical applications. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 149:105064. [PMID: 37734429 DOI: 10.1016/j.dci.2023.105064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 09/23/2023]
Abstract
The immune system is divided into two broad categories, consisting of innate and adaptive immunity. As recognition and effector factors of innate immunity and regulators of adaptive immune responses, lectins are considered to be important defense chemicals against microbial pathogens, cell trafficking, immune regulation, and prevention of autoimmunity. Pentraxins, important members of animal lectins, play a significant role in protecting the body from pathogen infection and regulating inflammatory reactions. They can recognize and bind to a variety of ligands, including carbohydrates, lipids, proteins, nucleic acids and their complexes, and protect the host from pathogen invasion by activating the complement cascade and Fcγ receptor pathways. Based on the primary structure of the subunit, pentraxins are divided into short and long pentraxins. The short pentraxins are comprised of C-reactive protein (CRP) and serum amyloid P (SAP), and the most important member of the long pentraxins is pentraxin 3 (PTX3). The CRP and SAP exist in both vertebrates and invertebrates, while the PTX3 may be present only in vertebrates. The major ligands and functions of CRP, SAP and PTX3 and three activation pathways involved in the complement system are summarized in this review. Their different characteristics in various animals including humans, and their evolutionary trees are analyzed. The clinical applications of CRP, SAP and PTX3 in human are reviewed. Some questions that remain to be understood are also highlighted.
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Affiliation(s)
- Yuying Wang
- School of Life Sciences, Ludong University, Yantai, 264025, People's Republic of China
| | - Wei Chen
- School of Life Sciences, Ludong University, Yantai, 264025, People's Republic of China; Yantai Productivity Promotion Center, Yantai, 264003, People's Republic of China
| | - Shuo Ding
- School of Life Sciences, Ludong University, Yantai, 264025, People's Republic of China
| | - Wenjun Wang
- School of Life Sciences, Ludong University, Yantai, 264025, People's Republic of China
| | - Changliu Wang
- School of Life Sciences, Ludong University, Yantai, 264025, People's Republic of China.
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8
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Li D, Hao Z, Nan Y, Chen Y. Role of long pentraxin PTX3 in cancer. Clin Exp Med 2023; 23:4401-4411. [PMID: 37438568 DOI: 10.1007/s10238-023-01137-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/05/2023] [Indexed: 07/14/2023]
Abstract
Cancer has become a leading cause of death and disease burden worldwide, closely related to rapid socioeconomic development. However, the fundamental reason is the lack of comprehensive understanding of the mechanism of cancer, accurate identification of preclinical cancer, and effective treatment of the disease. Therefore, it is particularly urgent to study specific mechanisms of cancer and develop effective prediction and treatment methods. Long Pentraxin PTX3 is a soluble pattern recognition molecule produced by various cells in inflammatory sites, which plays a role as a promoter or suppressor of cancer in multiple tumors through participating in innate immune response, neovascularization, energy metabolism, invasion, and metastasis mechanisms. Based on this, this article mainly reviews the role of PTX3 in various cancers.
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Affiliation(s)
- Duo Li
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
| | - Zhaozhao Hao
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
| | - Yandong Nan
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China.
| | - Yanwei Chen
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
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9
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Meri S, Magrini E, Mantovani A, Garlanda C. The Yin Yang of Complement and Cancer. Cancer Immunol Res 2023; 11:1578-1588. [PMID: 37902610 DOI: 10.1158/2326-6066.cir-23-0399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/07/2023] [Accepted: 09/12/2023] [Indexed: 10/31/2023]
Abstract
Cancer-related inflammation is a crucial component of the tumor microenvironment (TME). Complement activation occurs in cancer and supports the development of an inflammatory microenvironment. Complement has traditionally been considered a mechanism of immune resistance against cancer, and its activation is known to contribute to the cytolytic effects of antibody-based immunotherapeutic treatments. However, several studies have recently revealed that complement activation may exert protumoral functions by sustaining cancer-related inflammation and immunosuppression through different molecular mechanisms, targeting both the TME and cancer cells. These new discoveries have revealed that complement manipulation can be considered a new strategy for cancer therapies. Here we summarize our current understanding of the mechanisms by which the different elements of the complement system exert antitumor or protumor functions, both in preclinical studies and in human tumorigenesis. Complement components can serve as disease biomarkers for cancer stratification and prognosis and be exploited for tumor treatment.
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Affiliation(s)
- Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University and University Hospital of Helsinki, Helsinki, Finland
| | | | - Alberto Mantovani
- IRCCS-Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Cecilia Garlanda
- IRCCS-Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Qiu L, Li J, Bai H, Wang L, Zeng Q, Wu S, Li P, Mu L, Yin X, Ye J. Long-chain pentraxin 3 possesses agglutination activity and plays a role in host defense against bacterial infection in Oreochromis niloticus. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 149:105053. [PMID: 37657531 DOI: 10.1016/j.dci.2023.105053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/30/2023] [Accepted: 08/30/2023] [Indexed: 09/03/2023]
Abstract
Pentraxin 3 (PTX3) is a soluble pattern recognition molecule in the innate immune system that has multiple functions. It is involved in resisting pathogen infection. However, the functions of PTX3 in teleost fish are not well understood. In this study, we identified and characterized PTX3 in Nile tilapia (Oreochromis niloticus) (OnPTX3). The open reading frame of OnPTX3 was found to be 1305 bp, encoding 434 aa. We conducted spatial mRNA expression analysis and found that the expression of OnPTX3 was significantly increased after infection with Streptococcus agalactiae and Aeromonas hydrophila, both in vivo and in vitro. We also observed that recombinant OnPTX3 protein could bind and agglutinate bacterial pathogen. Furthermore, OnPTX3 enhanced the phagocytosis of bacteria (S. agalactiae and A. hydrophila) by head kidney macrophages. Additionally, OnPTX3 was found to influence the expression of inflammatory cytokines, suggesting its involvement in the regulation of the inflammatory response. Moreover, OnPTX3 was shown to promote complement-mediated hemolysis and possess antibacterial activity. In conclusion, our research demonstrates that OnPTX3 has bacterial binding and agglutination activities, enhances phagocytosis, and regulates inflammation. It plays a crucial role in the defense of Nile tilapia against pathogenic bacteria, providing valuable insights for the prevention and control of aquatic diseases in the future.
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Affiliation(s)
- Li Qiu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Jiadong Li
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Hao Bai
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Lili Wang
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Qingliang Zeng
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Siqi Wu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Peiyu Li
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China
| | - Liangliang Mu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China.
| | - Xiaoxue Yin
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China.
| | - Jianmin Ye
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, 510631, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 5a0642, PR China; Guangdong Provincial Engineering Technology Research Center for Environmentally-Friendly Aquaculture, South China Normal University, Guangzhou, 510631, PR China.
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11
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Massimino AM, Colella FE, Bottazzi B, Inforzato A. Structural insights into the biological functions of the long pentraxin PTX3. Front Immunol 2023; 14:1274634. [PMID: 37885881 PMCID: PMC10598717 DOI: 10.3389/fimmu.2023.1274634] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 09/27/2023] [Indexed: 10/28/2023] Open
Abstract
Soluble pattern recognition molecules (PRMs) are a heterogenous group of proteins that recognize pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively), and cooperate with cell-borne receptors in the orchestration of innate and adaptive immune responses to pathogenic insults and tissue damage. Amongst soluble PRMs, pentraxins are a family of highly conserved proteins with distinctive structural features. Originally identified in the early 1990s as an early inflammatory gene, PTX3 is the prototype of long pentraxins. Unlike the short pentraxin C reactive protein (CRP), whose expression is mostly confined to the liver, PTX3 is made by several immune and non-immune cells at sites of infection and inflammation, where it intercepts fundamental aspects of infection immunity, inflammation, and tissue remodeling. Of note, PTX3 cross talks to components of the complement system to control cancer-related inflammation and disposal of pathogens. Also, it is an essential component of inflammatory extracellular matrices (ECMs) through crosslinking of hyaluronic acid and turn-over of provisional fibrin networks that assemble at sites of tissue injury. This functional diversity is mediated by unique structural characteristics whose fine details have been unveiled only recently. Here, we revisit the structure/function relationships of this long pentraxin in light of the most recent advances in its structural biology, with a focus on the interplay with complement and the emerging roles as a component of the ECM. Differences to and similarities with the short pentraxins are highlighted and discussed.
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Affiliation(s)
| | | | - Barbara Bottazzi
- Laboratory of Cellular and Humoral Innate Immunity, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Antonio Inforzato
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Laboratory of Cellular and Humoral Innate Immunity, IRCCS Humanitas Research Hospital, Rozzano, Italy
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12
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Oliveira Cavalcanti E, Freitas Lidani KC, de Freitas Oliveira Toré C, de Messias Reason IJ, Andrade FA. MASP1 Gene Polymorphism and MASP-3 Serum Levels in Patients with Chronic Chagas Disease. Immunol Invest 2022; 51:2108-2121. [PMID: 36166216 DOI: 10.1080/08820139.2022.2110503] [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: 11/05/2022]
Abstract
INTRODUCTION Chagas disease (CD), caused by Trypanosoma cruzi, is a major public health issue worldwide affecting 6-7 million people, mainly in Latin America. The complement system plays a crucial role in host immune defense against T. cruzi infection and during the chronic phase of CD; however, the role of the MBL-associated serine protease 1 (MASP1) gene encoding MASP-1, MASP-3, and MAp44 complement proteins has not yet been reported in CD. This study investigated the possible association between MASP1 gene polymorphisms and MASP-3 protein serum levels in chronic CD and its clinical forms. METHODS Five polymorphisms of MASP1 gene regulatory regions were genotyped in 214 patients with CD and 197 healthy controls (rs7609662 G>A, rs13064994 C>T, rs72549262 C>G, rs1109452 C>T and rs850314 G>A). MASP-3 serum levels were assessed in 70 patients and 66 healthy controls. Clinical data, serum levels of complement proteins (ficolin-2, ficolin-3 and MBL) and inflammatory markers (pentraxin-3 and hsCRP) were also included in the analyses. RESULTS A significant association of the MASP1 GC_CCA haplotype with CD (padj= 0.002; OR 3.17 [1.19-8.39]) and chronic chagasic cardiomyopathy (CCC) (padj= 0.013; OR 4.57 [1.37-15.16] was observed. MASP-3 and pentraxin-3 levels were positively correlated in the patients (rho = 0.62; p = 0.0001). MASP-3 levels were not associated with MASP1 polymorphisms or CD and its clinical forms. Furthermore, no correlation was observed between MASP-3 levels and that of ficolin-2, ficolin-3, MBL and hsCRP. CONCLUSION Our findings suggest a possible role for the MASP1 GC_CCA haplotype in susceptibility to chronic CD and CCC clinical forms.
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Affiliation(s)
- Ednéia Oliveira Cavalcanti
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
| | - Kárita Cláudia Freitas Lidani
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil.,Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | | | - Fabiana Antunes Andrade
- Laboratory of Molecular Immunopathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil.,Department of Medicine, Positivo University, Curitiba, Brazil
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13
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Molecular insight into pentraxin-3: update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role. Biomed Pharmacother 2022; 156:113783. [PMID: 36240615 DOI: 10.1016/j.biopha.2022.113783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/28/2022] [Accepted: 09/28/2022] [Indexed: 11/20/2022] Open
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14
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PTX3 structure determination using a hybrid cryoelectron microscopy and AlphaFold approach offers insights into ligand binding and complement activation. Proc Natl Acad Sci U S A 2022; 119:e2208144119. [PMID: 35939690 PMCID: PMC9388099 DOI: 10.1073/pnas.2208144119] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Pattern recognition molecules (PRMs) form an important part of innate immunity, where they facilitate the response to infections and damage by triggering processes such as inflammation. The pentraxin family of soluble PRMs comprises long and short pentraxins, with the former containing unique N-terminal regions unrelated to other proteins or each other. No complete high-resolution structural information exists about long pentraxins, unlike the short pentraxins, where there is an abundance of both X-ray and cryoelectron microscopy (cryo-EM)-derived structures. This study presents a high-resolution structure of the prototypical long pentraxin, PTX3. Cryo-EM yielded a 2.5-Å map of the C-terminal pentraxin domains that revealed a radically different quaternary structure compared to other pentraxins, comprising a glycosylated D4 symmetrical octameric complex stabilized by an extensive disulfide network. The cryo-EM map indicated α-helices that extended N terminal of the pentraxin domains that were not fully resolved. AlphaFold was used to predict the remaining N-terminal structure of the octameric PTX3 complex, revealing two long tetrameric coiled coils with two hinge regions, which was validated using classification of cryo-EM two-dimensional averages. The resulting hybrid cryo-EM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and fibroblast growth factor-2, as well as rationalization of previous biochemical data. Given the relevance of PTX3 in conditions ranging from COVID-19 prognosis, cancer progression, and female infertility, this structure could be used to inform the understanding and rational design of therapies for these disorders and processes.
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15
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Välikangas T, Junttila S, Rytkönen KT, Kukkonen-Macchi A, Suomi T, Elo LL. COVID-19-specific transcriptomic signature detectable in blood across multiple cohorts. Front Genet 2022; 13:929887. [PMID: 35991542 PMCID: PMC9388772 DOI: 10.3389/fgene.2022.929887] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/27/2022] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading across the world despite vast global vaccination efforts. Consequently, many studies have looked for potential human host factors and immune mechanisms associated with the disease. However, most studies have focused on comparing COVID-19 patients to healthy controls, while fewer have elucidated the specific host factors distinguishing COVID-19 from other infections. To discover genes specifically related to COVID-19, we reanalyzed transcriptome data from nine independent cohort studies, covering multiple infections, including COVID-19, influenza, seasonal coronaviruses, and bacterial pneumonia. The identified COVID-19-specific signature consisted of 149 genes, involving many signals previously associated with the disease, such as induction of a strong immunoglobulin response and hemostasis, as well as dysregulation of cell cycle-related processes. Additionally, potential new gene candidates related to COVID-19 were discovered. To facilitate exploration of the signature with respect to disease severity, disease progression, and different cell types, we also offer an online tool for easy visualization of the selected genes across multiple datasets at both bulk and single-cell levels.
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Affiliation(s)
- Tommi Välikangas
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Sini Junttila
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Kalle T. Rytkönen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Anu Kukkonen-Macchi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Tomi Suomi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Laura L. Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Institute of Biomedicine, University of Turku, Turku, Finland
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16
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Rao RM, Dauchez M, Baud S. How molecular modelling can better broaden the understanding of glycosylations. Curr Opin Struct Biol 2022; 75:102393. [PMID: 35679802 DOI: 10.1016/j.sbi.2022.102393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/31/2022] [Accepted: 04/18/2022] [Indexed: 11/03/2022]
Abstract
Glycosylations are among the most ubiquitous post-translational modifications (PTMs) in proteins, and the effects of their perturbations are seen in various diseases such as cancers, diabetes and arthritis to name a few. Yet they remain one of the most enigmatic aspects of protein structure and function. On the other hand, molecular modelling techniques have been rapidly bridging this knowledge gap since the last decade. In this review, we discuss how these techniques have proven to be indispensable for a better understanding of the role of glycosylations in glycoprotein structure and function.
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Affiliation(s)
- Rajas M Rao
- Université de Reims Champagne Ardenne, CNRS UMR 7369, MEDyC, Reims, 51687, France
| | - Manuel Dauchez
- Université de Reims Champagne Ardenne, CNRS UMR 7369, MEDyC, Reims, 51687, France.
| | - Stéphanie Baud
- Université de Reims Champagne Ardenne, CNRS UMR 7369, MEDyC, Reims, 51687, France
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17
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Complement Factor H related protein 1 and immune inflammatory disorders. Mol Immunol 2022; 145:43-49. [DOI: 10.1016/j.molimm.2022.03.117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 11/24/2022]
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18
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Jonasdottir AD, Antovic A, Qureshi AR, Nordin A, Malmström V, Gunnarsson I, Bruchfeld A. Pentraxin-3 - a potential biomarker in ANCA-associated vasculitis. Scand J Rheumatol 2022; 52:293-301. [PMID: 35383519 DOI: 10.1080/03009742.2022.2045790] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE The aim of this study was to investigate pentraxin-3 (PTX3) as a potential biomarker of inflammatory activity in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at baseline and 6 month follow-up in a longitudinal cohort. METHOD Plasma PTX3 levels were measured in 79 newly diagnosed or relapsing AAV patients at baseline and 6 month follow-up, and in 23 healthy controls. Urinary PTX3 levels were measured in 34 of the patients. C-reactive protein (CRP), creatinine, and albuminuria were measured and the cumulative glucocorticoid dose at inclusion was calculated. The Birmingham Vasculitis Activity Score (BVAS) was assessed at baseline and follow-up. RESULTS Plasma PTX3 levels were significantly higher at baseline than at 6 months (2.85 vs 1.23 ng/mL, p < 0.001). Plasma and urinary PTX3 levels correlated with BVAS at baseline (ρ = 0.45, p < 0.001, and ρ = 0.49, p = 0.008, respectively). A significant correlation between both plasma and urinary PTX3 levels and estimated glomerular filtration rate and albuminuria was found. However, there was no correlation between plasma and urinary PTX3 levels. At baseline, plasma and urinary PTX3 levels were significantly higher in patients with kidney involvement. PTX3 levels did not correlate with CRP, nor was there a correlation between CRP levels and BVAS at baseline. CONCLUSION Plasma and urinary PTX3 seem to reflect disease activity in AAV better than the commonly used CRP. PTX3 may have a potential role as a biomarker in monitoring disease activity in AAV patients, particularly in patients with kidney involvement.
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Affiliation(s)
- A D Jonasdottir
- Division of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden.,Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - A Antovic
- Department of Medicine, Division of Rheumatology Solna, Karolinska Institutet, Stockholm, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - A R Qureshi
- Baxter Novum, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - A Nordin
- Department of Medicine, Division of Rheumatology Solna, Karolinska Institutet, Stockholm, Sweden
| | - V Malmström
- Department of Medicine, Division of Rheumatology Solna, Karolinska Institutet, Stockholm, Sweden
| | - I Gunnarsson
- Department of Medicine, Division of Rheumatology Solna, Karolinska Institutet, Stockholm, Sweden.,Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - A Bruchfeld
- Division of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden.,Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden.,Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
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19
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Stravalaci M, Ferrara M, Pathak V, Davi F, Bottazzi B, Mantovani A, Medina RJ, Romano MR, Inforzato A. The Long Pentraxin PTX3 as a New Biomarker and Pharmacological Target in Age-Related Macular Degeneration and Diabetic Retinopathy. Front Pharmacol 2022; 12:811344. [PMID: 35069222 PMCID: PMC8776640 DOI: 10.3389/fphar.2021.811344] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/20/2021] [Indexed: 12/12/2022] Open
Abstract
Age related macular degeneration (AMD) and diabetic retinopathy (DR) are multifactorial, neurodegenerative and inflammatory diseases of the eye primarily involving cellular and molecular components of the outer and inner blood-retina barriers (BRB), respectively. Largely contributed by genetic factors, particularly polymorphisms in complement genes, AMD is a paradigm of retinal immune dysregulation. DR, a major complication of diabetes mellitus, typically presents with increased vascular permeability and occlusion of the retinal vasculature that leads, in the proliferative form of the disease, to neovascularization, a pathogenic trait shared with advanced AMD. In spite of distinct etiology and clinical manifestations, both pathologies share common drivers, such as chronic inflammation, either of immune (in AMD) or metabolic (in DR) origin, which initiates and propagates degeneration of the neural retina, yet the underlying mechanisms are still unclear. As a soluble pattern recognition molecule with complement regulatory functions and a marker of vascular damage, long pentraxin 3 (PTX3) is emerging as a novel player in ocular homeostasis and a potential pharmacological target in neurodegenerative disorders of the retina. Physiologically present in the human eye and induced in inflammatory conditions, this protein is strategically positioned at the BRB interface, where it acts as a “molecular trap” for complement, and modulates inflammation both in homeostatic and pathological conditions. Here, we discuss current viewpoints on PTX3 and retinal diseases, with a focus on AMD and DR, the roles therein proposed for this pentraxin, and their implications for the development of new therapeutic strategies.
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Affiliation(s)
| | | | - Varun Pathak
- School of Medicine, Dentistry, and Biomedical Sciences, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
| | | | | | - Alberto Mantovani
- IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Reinhold J Medina
- School of Medicine, Dentistry, and Biomedical Sciences, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Mario R Romano
- Eye Center, Humanitas Gavazzeni-Castelli, Bergamo, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
| | - Antonio Inforzato
- IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Italy
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20
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Severity Biomarkers in Puumala Hantavirus Infection. Viruses 2021; 14:v14010045. [PMID: 35062248 PMCID: PMC8778356 DOI: 10.3390/v14010045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/16/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
Annually, over 10,000 cases of hemorrhagic fever with renal syndrome (HFRS) are diagnosed in Europe. Puumala hantavirus (PUUV) causes most of the European HFRS cases. PUUV causes usually a relatively mild disease, which is rarely fatal. However, the severity of the infection varies greatly, and factors affecting the severity are mostly unrevealed. Host genes are known to have an effect. The typical clinical features in PUUV infection include acute kidney injury, thrombocytopenia, and increased vascular permeability. The primary target of hantavirus is the endothelium of the vessels of different organs. Although PUUV does not cause direct cytopathology of the endothelial cells, remarkable changes in both the barrier function of the endothelium and the function of the infected endothelial cells occur. Host immune or inflammatory mechanisms are probably important in the development of the capillary leakage. Several immunoinflammatory biomarkers have been studied in the context of assessing the severity of HFRS caused by PUUV. Most of them are not used in clinical practice, but the increasing knowledge about the biomarkers has elucidated the pathogenesis of PUUV infection.
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21
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Parente R, Possetti V, Erreni M, D'Autilia F, Bottazzi B, Garlanda C, Mantovani A, Inforzato A, Doni A. Complementary Roles of Short and Long Pentraxins in the Complement-Mediated Immune Response to Aspergillus fumigatus Infections. Front Immunol 2021; 12:785883. [PMID: 34868070 PMCID: PMC8637271 DOI: 10.3389/fimmu.2021.785883] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/01/2021] [Indexed: 01/08/2023] Open
Abstract
The ubiquitous mold Aspergillus fumigatus is the major etiologic agent of invasive aspergillosis, a life-threatening infection amongst immune compromised individuals. An increasing body of evidence indicates that effective disposal of A. fumigatus requires the coordinate action of both cellular and humoral components of the innate immune system. Early recognition of the fungal pathogen, in particular, is mediated by a set of diverse soluble pattern recognition molecules (PRMs) that act as "ancestral antibodies" inasmuch as they are endowed with opsonic, pro-phagocytic and killing properties. Pivotal is, in this respect, the contribution of the complement system, which functionally cooperates with cell-borne pattern recognition receptors (PRRs) and other soluble PRMs, including pentraxins. Indeed, complement and pentraxins form an integrated system with crosstalk, synergism, and regulation, which stands as a paradigm of the interplay between PRMs in the mounting and orchestration of antifungal immunity. Following upon our past experience with the long pentraxin PTX3, a well-established immune effector in the host response to A. fumigatus, we recently reported that this fungal pathogen is targeted in vitro and in vivo by the short pentraxin Serum Amyloid P component (SAP) too. Similar to PTX3, SAP promotes phagocytosis and disposal of the fungal pathogen via complement-dependent pathways. However, the two proteins exploit different mechanisms of complement activation and receptor-mediated phagocytosis, which further extends complexity and integration of the complement-pentraxin crosstalk in the immune response to A. fumigatus. Here we revisit this crosstalk in light of the emerging roles of SAP as a novel PRM with antifungal activity.
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Affiliation(s)
- Raffaella Parente
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Valentina Possetti
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Marco Erreni
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Francesca D'Autilia
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Barbara Bottazzi
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Cecilia Garlanda
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Alberto Mantovani
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Antonio Inforzato
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Andrea Doni
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
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22
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Kárpáti É, Kremlitzka M, Sándor N, Hajnal D, Schneider AE, Józsi M. Complement Factor H Family Proteins Modulate Monocyte and Neutrophil Granulocyte Functions. Front Immunol 2021; 12:660852. [PMID: 34671340 PMCID: PMC8521052 DOI: 10.3389/fimmu.2021.660852] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 09/07/2021] [Indexed: 01/13/2023] Open
Abstract
Besides being a key effector arm of innate immunity, a plethora of non-canonical functions of complement has recently been emerging. Factor H (FH), the main regulator of the alternative pathway of complement activation, has been reported to bind to various immune cells and regulate their functions, beyond its role in modulating complement activation. In this study we investigated the effect of FH, its alternative splice product FH-like protein 1 (FHL-1), the FH-related (FHR) proteins FHR-1 and FHR-5, and the recently developed artificial complement inhibitor mini-FH, on two key innate immune cells, monocytes and neutrophilic granulocytes. We found that, similar to FH, the other factor H family proteins FHL-1, FHR-1 and FHR-5, as well as the recombinant mini-FH, are able to bind to both monocytes and neutrophils. As a functional outcome, immobilized FH and FHR-1 inhibited PMA-induced NET formation, but increased the adherence and IL-8 production of neutrophils. FHL-1 increased only the adherence of the cells, while FHR-5 was ineffective in altering these functions. The adherence of monocytes was increased on FH, recombinant mini-FH and FHL-1 covered surfaces and, except for FHL-1, the same molecules also enhanced secretion of the inflammatory cytokines IL-1β and TNFα. When monocytes were stimulated with LPS in the presence of immobilized FH family proteins, FH, FHL-1 and mini-FH enhanced whereas FHR-1 and FHR-5 decreased the secretion of TNFα; FHL-1 and mini-FH also enhanced IL-10 release compared to the effect of LPS alone. Our results reveal heterogeneous effects of FH and FH family members on monocytes and neutrophils, altering key features involved in pathogen killing, and also demonstrate that FH-based complement inhibitors, such as mini-FH, may have effects beyond their function of inhibiting complement activation. Thus, our data provide new insight into the non-canonical functions of FH, FHL-1, FHR-1 and FHR-5 that might be exploited during protection against infections and in vaccine development.
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Affiliation(s)
- Éva Kárpáti
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mariann Kremlitzka
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Noémi Sándor
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dávid Hajnal
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Andrea E Schneider
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Eötvös Loránd Research Network (ELKH), Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
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23
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Coagulopathy in Acute Puumala Hantavirus Infection. Viruses 2021; 13:v13081553. [PMID: 34452419 PMCID: PMC8402851 DOI: 10.3390/v13081553] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/26/2022] Open
Abstract
Puumala hantavirus (PUUV) causes a hemorrhagic fever with renal syndrome (HFRS), also called nephropathia epidemica (NE), which is mainly endemic in Europe and Russia. The clinical features include a low platelet count, altered coagulation, endothelial activation, and acute kidney injury (AKI). Multiple connections between coagulation pathways and inflammatory mediators, as well as complement and kallikrein–kinin systems, have been reported. The bleeding symptoms are usually mild. PUUV-infected patients also have an increased risk for disseminated intravascular coagulation (DIC) and thrombosis.
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24
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Koussih L, Atoui S, Tliba O, Gounni AS. New Insights on the Role of pentraxin-3 in Allergic Asthma. FRONTIERS IN ALLERGY 2021; 2:678023. [PMID: 35387000 PMCID: PMC8974764 DOI: 10.3389/falgy.2021.678023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 05/06/2021] [Indexed: 11/13/2022] Open
Abstract
Pentraxins are soluble pattern recognition receptors that play a major role in regulating innate immune responses. Through their interaction with complement components, Fcγ receptors, and different microbial moieties, Pentraxins cause an amplification of the inflammatory response. Pentraxin-3 is of particular interest since it was identified as a biomarker for several immune-pathological diseases. In allergic asthma, pentraxin-3 is produced by immune and structural cells and is up-regulated by pro-asthmatic cytokines such as TNFα and IL-1β. Strikingly, some recent experimental evidence demonstrated a protective role of pentraxin-3 in chronic airway inflammatory diseases such as allergic asthma. Indeed, reduced pentraxin-3 levels have been associated with neutrophilic inflammation, Th17 immune response, insensitivity to standard therapeutics and a severe form of the disease. In this review, we will summarize the current knowledge of the role of pentraxin-3 in innate immune response and discuss the protective role of pentraxin-3 in allergic asthma.
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Affiliation(s)
- Latifa Koussih
- Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Department des Sciences Experimentales, Universite de Saint-Boniface, Winnipeg, MB, Canada
| | - Samira Atoui
- Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Omar Tliba
- Department of Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY, United States
| | - Abdelilah S. Gounni
- Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- *Correspondence: Abdelilah S. Gounni
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25
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Gutmann C, Takov K, Burnap SA, Singh B, Ali H, Theofilatos K, Reed E, Hasman M, Nabeebaccus A, Fish M, McPhail MJ, O'Gallagher K, Schmidt LE, Cassel C, Rienks M, Yin X, Auzinger G, Napoli S, Mujib SF, Trovato F, Sanderson B, Merrick B, Niazi U, Saqi M, Dimitrakopoulou K, Fernández-Leiro R, Braun S, Kronstein-Wiedemann R, Doores KJ, Edgeworth JD, Shah AM, Bornstein SR, Tonn T, Hayday AC, Giacca M, Shankar-Hari M, Mayr M. SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care. Nat Commun 2021; 12:3406. [PMID: 34099652 PMCID: PMC8184784 DOI: 10.1038/s41467-021-23494-1] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 04/28/2021] [Indexed: 02/05/2023] Open
Abstract
Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
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Affiliation(s)
- Clemens Gutmann
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Kaloyan Takov
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Sean A Burnap
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Bhawana Singh
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Hashim Ali
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Konstantinos Theofilatos
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Ella Reed
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Maria Hasman
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Adam Nabeebaccus
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
- King's College Hospital NHS Foundation Trust, London, UK
| | - Matthew Fish
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
- Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Mark Jw McPhail
- King's College Hospital NHS Foundation Trust, London, UK
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Kevin O'Gallagher
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
- King's College Hospital NHS Foundation Trust, London, UK
| | - Lukas E Schmidt
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Christian Cassel
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Marieke Rienks
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Xiaoke Yin
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Georg Auzinger
- King's College Hospital NHS Foundation Trust, London, UK
| | - Salvatore Napoli
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Salma F Mujib
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Francesca Trovato
- King's College Hospital NHS Foundation Trust, London, UK
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Barnaby Sanderson
- Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Blair Merrick
- Clinical Infection and Diagnostics Research group, Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Umar Niazi
- NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Mansoor Saqi
- NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Konstantina Dimitrakopoulou
- NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
| | - Rafael Fernández-Leiro
- Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Silke Braun
- Medical Clinic I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Romy Kronstein-Wiedemann
- Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany
| | - Katie J Doores
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Jonathan D Edgeworth
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
- Clinical Infection and Diagnostics Research group, Department of Infection, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Ajay M Shah
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
- King's College Hospital NHS Foundation Trust, London, UK
| | - Stefan R Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
- Department of Diabetes, School of Life Course Science and Medicine, King's College London, London, UK
| | - Torsten Tonn
- Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany
- Institute for Transfusion Medicine, German Red Cross Blood Donation Service North East, Dresden, Germany
| | - Adrian C Hayday
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK
- The Francis Crick Institute, London, UK
| | - Mauro Giacca
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Manu Shankar-Hari
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.
- Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK.
| | - Manuel Mayr
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
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26
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Li K, Mo W, Wu L, Wu X, Luo C, Xiao X, Jia X, Yang H, Fei Y, Chen H, Zhang F, Li Y, Zhao L, Zhang X. Novel autoantibodies identified in ACPA-negative rheumatoid arthritis. Ann Rheum Dis 2021; 80:739-747. [PMID: 33452006 DOI: 10.1136/annrheumdis-2020-218460] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Lack of effective biomarkers in anti-citrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA) impedes early diagnosis and treatment. This study aimed to identify novel autoantibodies in RA and verify their diagnostic values in ACPA-negative RA based on protein microarray technology. METHODS A total of 1011 sera from 559 RA (276 ACPA-positive and 283 ACPA-negative), 239 disease controls (DCs) and 213 healthy controls (HCs) were collected and sampled on two sequential microarrays and ELISA and western blot (WB) detection, for novel autoantibodies discovery, validation and verification, respectively. The high-density protein microarray printed with a broad spectrum of recombinant human proteins was first employed to screen candidate autoantibodies, then focused microarrays composed of candidate autoantigens were used for validation, followed by ELISA and WB to verify the presence of the most promising candidates in ACPA-negative RA. RESULTS Nine novel autoantibodies were identified by two sequential microarrays with positivity 17.93%-27.59% and specificities >90% in ACPA-negative RA. Among these, anti-PTX3 and anti-DUSP11 autoantibodies presented with the highest sensitivity and were consistently verified by ELISA and WB. Pooling samples of all cohorts, the positivities of anti-PTX3 and anti-DUSP11 in ACPA-negative RA were 27.56% and 31.80%, respectively, similar to those in ACPA-positive RA, and significantly higher than in HCs (4.69% and 2.35%) and DCs (10.04% and 8.49%) (p<0.0001). Combination of anti-PTX3 with anti-DUSP11 significantly increased the diagnostic sensitivity (38.00%) with specificity of 88.72%, regardless of ACPA status. CONCLUSION Anti-PTX3 and anti-DUSP11 autoantibodies are newly identified biomarkers for diagnosis of ACPA-negative RA.
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Affiliation(s)
- Ketian Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Wenxiu Mo
- Department of Rheumatology and Immunology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Lijun Wu
- Department of Rheumatology and Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Xunyao Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Cainan Luo
- Department of Rheumatology and Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Xinyue Xiao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Xinmiao Jia
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Huaxia Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Yunyun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Yongzhe Li
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
| | - Xuan Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Dongcheng-qu, Beijing, China
- Clinical Immunology Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng-qu, Beijing, China
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27
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Asgari F, Supino D, Parente R, Polentarutti N, Stravalaci M, Porte R, Pasqualini F, Barbagallo M, Perucchini C, Recordati C, Magrini E, Mariancini A, Riva F, Giordano A, Davoudian S, Roger T, Veer CV, Jaillon S, Mantovani A, Doni A, Garlanda C. The Long Pentraxin PTX3 Controls Klebsiella Pneumoniae Severe Infection. Front Immunol 2021; 12:666198. [PMID: 34093560 PMCID: PMC8173212 DOI: 10.3389/fimmu.2021.666198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 05/04/2021] [Indexed: 12/29/2022] Open
Abstract
Klebsiella pneumoniae is a common pathogen in human sepsis. The emergence of multidrug-resistant K. pneumoniae strains represents a major clinical challenge in nosocomial and community acquired infections. The long pentraxin PTX3, a key component of humoral innate immunity, is involved in resistance to selected pathogens by promoting opsonophagocytosis. We investigated the relevance of PTX3 in innate immunity against K. pneumoniae infections using Ptx3-/- mice and mouse models of severe K. pneumoniae infections. Local and systemic PTX3 expression was induced following K. pneumoniae pulmonary infection, in association with the up-regulation of TNF-α and IL-1β. PTX3 deficiency in mice was associated with higher bacterial burden and mortality, release of pro-inflammatory cytokines as well as IL-10 in the lung and systemically. The analysis of the mechanisms responsible of PTX3-dependent control of K. pneumoniae infection revealed that PTX3 did not interact with K. pneumoniae, or promote opsonophagocytosis. The comparison of susceptibility of wild-type, Ptx3-/-, C3-/- and Ptx3-/-/C3-/- mice to the infection showed that PTX3 acted in a complement-independent manner. Lung histopathological analysis showed more severe lesions in Ptx3-/- mice with fibrinosuppurative, necrotizing and haemorrhagic bronchopneumonia, associated with increased fibrin deposition in the lung and circulating fibrinogen consumption. These findings indicate that PTX3 contributes to the control of K. pneumoniae infection by modulating inflammatory responses and tissue damage. Thus, this study emphasizes the relevance of the role of PTX3 as regulator of inflammation and orchestrator of tissue repair in innate responses to infections.
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Affiliation(s)
- Fatemeh Asgari
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Domenico Supino
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Raffaella Parente
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Nadia Polentarutti
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Matteo Stravalaci
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Remi Porte
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Fabio Pasqualini
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Marialuisa Barbagallo
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Chiara Perucchini
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Camilla Recordati
- Department of Veterinary Medicine, University of Milano, Lodi, Italy
| | - Elena Magrini
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Andrea Mariancini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Federica Riva
- Department of Veterinary Medicine, University of Milano, Lodi, Italy
| | - Alessia Giordano
- Department of Veterinary Medicine, University of Milano, Lodi, Italy
| | - Sadaf Davoudian
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Epalinges, Switzerland
| | - Cornelis Van't Veer
- Center of Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, Netherlands
| | - Sebastien Jaillon
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Alberto Mantovani
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.,Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Andrea Doni
- Unit of Advanced Optical Microscopy, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Cecilia Garlanda
- Department of Inflammation and Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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28
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Maccarinelli F, Bugatti M, Churruca Schuind A, Ganzerla S, Vermi W, Presta M, Ronca R. Endogenous Long Pentraxin 3 Exerts a Protective Role in a Murine Model of Pulmonary Fibrosis. Front Immunol 2021; 12:617671. [PMID: 33679758 PMCID: PMC7930377 DOI: 10.3389/fimmu.2021.617671] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/11/2021] [Indexed: 12/14/2022] Open
Abstract
Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient Ptx3−/− animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, Ptx3-null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease.
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Affiliation(s)
- Federica Maccarinelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Mattia Bugatti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.,ASST Spedali Civili di Brescia, Brescia, Italy
| | - Ander Churruca Schuind
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | | | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.,ASST Spedali Civili di Brescia, Brescia, Italy
| | - Marco Presta
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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29
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Brilland B, Vinatier E, Subra JF, Jeannin P, Augusto JF, Delneste Y. Anti-Pentraxin Antibodies in Autoimmune Diseases: Bystanders or Pathophysiological Actors? Front Immunol 2021; 11:626343. [PMID: 33664737 PMCID: PMC7921723 DOI: 10.3389/fimmu.2020.626343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/29/2020] [Indexed: 11/16/2022] Open
Abstract
Pentraxins are soluble innate immunity receptors involved in sensing danger molecules. They are classified as short (CRP, SAP) and long pentraxin subfamilies, including the prototypic long pentraxin PTX3. Pentraxins act mainly as bridging molecules favoring the clearance of microbes and dead cells. They are also involved in many other biological processes, such as regulation of complement activation, inflammation and tissue homeostasis. Autoantibodies directed against pentraxins have been reported in various autoimmune diseases, especially in systemic lupus erythematosus and ANCA-associated vasculitis. In this review, we review the main biological characteristics and functions of pentraxins and summarize data concerning autoantibodies directed against pentraxins in the context of autoimmune diseases and discuss their potential pathological role.
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Affiliation(s)
- Benoit Brilland
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France.,Université d'Angers, INSERM, CRCINA, Angers, France
| | - Emeline Vinatier
- Université d'Angers, INSERM, CRCINA, Angers, France.,CHU Angers, Service d'Immunologie et Allergologie, Angers, France
| | - Jean-François Subra
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France.,Université d'Angers, INSERM, CRCINA, Angers, France
| | - Pascale Jeannin
- Université d'Angers, INSERM, CRCINA, Angers, France.,CHU Angers, Service d'Immunologie et Allergologie, Angers, France
| | - Jean-François Augusto
- CHU Angers, Service de Néphrologie-Dialyse-Transplantation, Angers, France.,Université d'Angers, INSERM, CRCINA, Angers, France
| | - Yves Delneste
- Université d'Angers, INSERM, CRCINA, Angers, France.,CHU Angers, Service d'Immunologie et Allergologie, Angers, France
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30
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Raposo CD, Canelas AB, Barros MT. Human Lectins, Their Carbohydrate Affinities and Where to Find Them. Biomolecules 2021; 11:188. [PMID: 33572889 PMCID: PMC7911577 DOI: 10.3390/biom11020188] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/02/2021] [Accepted: 01/26/2021] [Indexed: 12/20/2022] Open
Abstract
Lectins are a class of proteins responsible for several biological roles such as cell-cell interactions, signaling pathways, and several innate immune responses against pathogens. Since lectins are able to bind to carbohydrates, they can be a viable target for targeted drug delivery systems. In fact, several lectins were approved by Food and Drug Administration for that purpose. Information about specific carbohydrate recognition by lectin receptors was gathered herein, plus the specific organs where those lectins can be found within the human body.
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Affiliation(s)
- Cláudia D. Raposo
- LAQV-Requimte, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;
| | - André B. Canelas
- Glanbia-AgriChemWhey, Lisheen Mine, Killoran, Moyne, E41 R622 Tipperary, Ireland;
| | - M. Teresa Barros
- LAQV-Requimte, Department of Chemistry, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;
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31
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Qiu C, Han Y, Zhang H, Liu T, Hou H, Luo D, Yu M, Bian K, Zhao Y, Xiao X. Perspectives on long pentraxin 3 and rheumatoid arthritis: several potential breakthrough points relying on study foundation of the past. Int J Med Sci 2021; 18:1886-1898. [PMID: 33746606 PMCID: PMC7976587 DOI: 10.7150/ijms.54787] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/24/2021] [Indexed: 12/27/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic chronic autoimmune inflammatory disease which is mainly characterized by synovitis and results in a severe burden for both the individual and society. To date, the underlying mechanisms of RA are still poorly understood. Pentraxin 3 (PTX3) is a typical long pentraxin protein which has been highly conserved during evolution. Meanwhile, functions as well as properties of PTX3 have been extensively studied. Several studies identified that PTX3 plays a predominate role in infection, inflammation, immunity and tumor. Interestingly, PTX3 has also been verified to be closely associated with development of RA. We therefore accomplished an elaboration of the relationships between PTX3 and RA. Herein, we mainly focus on the associated cell types and cognate cytokines involved in RA, in combination with PTX3. This review infers the insight into the interaction of PTX3 in RA and aims to provide novel clues for potential therapeutic target of RA in clinic.
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Affiliation(s)
- Cheng Qiu
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China.,Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China.,Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Yichao Han
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China.,Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Hanwen Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China.,Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Tianyi Liu
- Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Haodong Hou
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China.,Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Dan Luo
- College of Stomatology, Qingdao University, Qingdao 266071, Shandong, P. R. China
| | - Mingzhi Yu
- Key Laboratory of High Efficiency and Clean Manufacturing, School of Mechanical Engineering, Shandong University, Jinan 250061, Shandong, P. R. China
| | - Kai Bian
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China.,Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Yunpeng Zhao
- Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, P. R. China
| | - Xing Xiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, P. R. China
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32
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Hevey R, Pouw RB, Harris C, Ricklin D. Sweet turning bitter: Carbohydrate sensing of complement in host defence and disease. Br J Pharmacol 2020; 178:2802-2822. [PMID: 33140840 DOI: 10.1111/bph.15307] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/20/2020] [Accepted: 10/26/2020] [Indexed: 12/27/2022] Open
Abstract
The complement system plays a major role in threat recognition and in orchestrating responses to microbial intruders and accumulating debris. This immune surveillance is largely driven by lectins that sense carbohydrate signatures on foreign, diseased and healthy host cells and act as complement activators, regulators or receptors to shape appropriate immune responses. While carbohydrate sensing protects our bodies, misguided or impaired recognition can contribute to disease. Moreover, pathogenic microbes have evolved to evade complement by mimicking host signatures. While complement is recognized as a disease factor, we only slowly start to appreciate the role of carbohydrate interactions in the underlying processes. A better understanding of complement's sweet side will contribute to a better description of disease mechanisms and enhanced diagnostic and therapeutic options. This review introduces the key components in complement-mediated carbohydrate sensing, discusses their role in health and disease, and touches on the potential effects of carbohydrate-related disease intervention. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Affiliation(s)
- Rachel Hevey
- Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Richard B Pouw
- Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Claire Harris
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Ricklin
- Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
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33
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Stravalaci M, Davi F, Parente R, Gobbi M, Bottazzi B, Mantovani A, Day AJ, Clark SJ, Romano MR, Inforzato A. Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration. Front Pharmacol 2020; 11:591908. [PMID: 33324220 PMCID: PMC7725797 DOI: 10.3389/fphar.2020.591908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/28/2020] [Indexed: 12/28/2022] Open
Abstract
Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H (CFH) gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a “hot spot” for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.
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Affiliation(s)
- Matteo Stravalaci
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy
| | - Francesca Davi
- Humanitas Clinical and Research Center IRCCS, Milan, Italy
| | | | - Marco Gobbi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | - Alberto Mantovani
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Anthony J Day
- Wellcome Trust Centre for Cell-Matrix Research and Lydia Becker Institute of Immunology and Inflammation, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Simon J Clark
- Universitäts-Augenklinik Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany.,The Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Mario R Romano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Eye Center, Humanitas Gavazzeni-Castelli, Bergamo, Italy
| | - Antonio Inforzato
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center IRCCS, Milan, Italy
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34
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Brunetta E, Folci M, Bottazzi B, De Santis M, Gritti G, Protti A, Mapelli SN, Bonovas S, Piovani D, Leone R, My I, Zanon V, Spata G, Bacci M, Supino D, Carnevale S, Sironi M, Davoudian S, Peano C, Landi F, Di Marco F, Raimondi F, Gianatti A, Angelini C, Rambaldi A, Garlanda C, Ciccarelli M, Cecconi M, Mantovani A. Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19. Nat Immunol 2020; 22:19-24. [PMID: 33208929 DOI: 10.1038/s41590-020-00832-x] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023]
Abstract
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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Affiliation(s)
- Enrico Brunetta
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marco Folci
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | | | - Giuseppe Gritti
- Unit of Hematology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Alessandro Protti
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | - Stefanos Bonovas
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Daniele Piovani
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Roberto Leone
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Ilaria My
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Veronica Zanon
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | | | - Monica Bacci
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Domenico Supino
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia Carnevale
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marina Sironi
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | | | - Clelia Peano
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Milan, Italy
| | - Francesco Landi
- Unit of Hematology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Fabiano Di Marco
- Unit of Pneumology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.,Department of Health Sciences, University of Milan, Milan, Italy
| | - Federico Raimondi
- Unit of Pneumology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Andrea Gianatti
- Unit of Pathology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | | | - Alessandro Rambaldi
- Unit of Hematology, Azienda Ospedaliera Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. .,Department of Oncology & Hemato-Oncology, University of Milan, Milan, Italy.
| | - Cecilia Garlanda
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy. .,Department of Biomedical Sciences, Humanitas University, Milan, Italy.
| | | | - Maurizio Cecconi
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy. .,Department of Biomedical Sciences, Humanitas University, Milan, Italy.
| | - Alberto Mantovani
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy. .,Department of Biomedical Sciences, Humanitas University, Milan, Italy. .,The William Harvey Research Institute, Queen Mary University of London, London, UK.
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35
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Tzoumas N, Hallam D, Harris CL, Lako M, Kavanagh D, Steel DHW. Revisiting the role of factor H in age-related macular degeneration: Insights from complement-mediated renal disease and rare genetic variants. Surv Ophthalmol 2020; 66:378-401. [PMID: 33157112 DOI: 10.1016/j.survophthal.2020.10.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022]
Abstract
Ophthalmologists are long familiar with the eye showing signs of systemic disease, but the association between age-related macular degeneration and abnormal complement activation, common to several renal disorders, has only recently been elucidated. Although complement activation products were identified in drusen almost three decades ago, it was not until the early 21st century that a single-nucleotide polymorphism in the complement factor H gene was identified as a major heritable determinant of age-related macular degeneration, galvanizing global efforts to unravel the pathogenesis of this common disease. Advances in proteomic analyses and familial aggregation studies have revealed distinctive clinical phenotypes segregated by the functional effects of common and rare genetic variants on the mature protein and its splice variant, factor H-like protein 1. The predominance of loss-of-function, N-terminal mutations implicate age-related macular degeneration as a disease of general complement dysregulation, offering several therapeutic avenues for its modulation. Here, we explore the molecular impact of these mutations/polymorphisms on the ability of variant factor H/factor H-like protein 1 to localize to polyanions, pentraxins, proinflammatory triggers, and cell surfaces across ocular and renal tissues and exert its multimodal regulatory functions and their clinical implications. Finally, we critically evaluate key therapeutic and diagnostic efforts in this rapidly evolving field.
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Affiliation(s)
- Nikolaos Tzoumas
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
| | - Dean Hallam
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Claire L Harris
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Majlinda Lako
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - David Kavanagh
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - David H W Steel
- Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Sunderland Eye Infirmary, Sunderland, United Kingdom
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36
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Smole U, Kratzer B, Pickl WF. Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces. Eur J Immunol 2020; 50:624-642. [PMID: 32246830 PMCID: PMC7216992 DOI: 10.1002/eji.201847811] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/25/2020] [Accepted: 03/31/2020] [Indexed: 01/08/2023]
Abstract
Maintenance of homeostasis at body barriers that are constantly challenged by microbes, toxins and potentially bioactive (macro)molecules requires complex, highly orchestrated mechanisms of protection. Recent discoveries in respiratory research have shed light on the unprecedented role of airway epithelial cells (AEC), which, besides immune cells homing to the lung, also significantly contribute to host defence by expressing membrane‐bound and soluble pattern recognition receptors (sPRR). Recent evidence suggests that distinct, evolutionary ancient, sPRR secreted by AEC might become activated by usually innocuous proteins, commonly referred to as allergens. We here provide a systematic overview on sPRR detectable in the mucus lining of AEC. Some of them become actively produced and secreted by AECs (like the pentraxins C‐reactive protein and pentraxin 3; the collectins mannose binding protein and surfactant proteins A and D; H‐ficolin; serum amyloid A; and the complement components C3 and C5). Others are elaborated by innate and adaptive immune cells such as monocytes/macrophages and T cells (like the pentraxins C‐reactive protein and pentraxin 3; L‐ficolin; serum amyloid A; and the complement components C3 and C5). Herein we discuss how sPRRs may contribute to homeostasis but sometimes also to overt disease (e.g. airway hyperreactivity and asthma) at the alveolar–air interface.
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Affiliation(s)
- Ursula Smole
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Bernhard Kratzer
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
| | - Winfried F. Pickl
- Institute of ImmunologyCenter for PathophysiologyInfectiology and ImmunologyMedical University of ViennaViennaAustria
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37
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Kárpáti É, Papp A, Schneider AE, Hajnal D, Cserhalmi M, Csincsi ÁI, Uzonyi B, Józsi M. Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization. Front Immunol 2020; 11:1297. [PMID: 32765490 PMCID: PMC7378360 DOI: 10.3389/fimmu.2020.01297] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022] Open
Abstract
Complement plays an essential role in the opsonophagocytic clearance of apoptotic/necrotic cells. Dysregulation of this process may lead to inflammatory and autoimmune diseases. Factor H (FH), a major soluble complement inhibitor, binds to dead cells and inhibits excessive complement activation on their surface, preventing lysis, and the release of intracellular material, including DNA. The FH-related (FHR) proteins share common ligands with FH, due to their homology with this complement regulator, but they lack the domains that mediate the complement inhibitory activity of FH. Because their roles in complement regulation is controversial and incompletely understood, we studied the interaction of FHR-1 and FHR-5 with DNA and dead cells and investigated whether they influence the regulatory role of FH and the complement activation on DNA and dead cells. FH, FHR-1, and FHR-5 bound to both plasmid DNA and human genomic DNA, where both FHR proteins inhibited FH-DNA interaction. The FH cofactor activity was inhibited by FHR-1 and FHR-5 due to the reduced binding of FH to DNA in the presence of the FHRs. Both FHRs caused increased complement activation on DNA. FHR-1 and FHR-5 bound to late apoptotic and necrotic cells and recruited monomeric C-reactive protein and pentraxin 3, and vice versa. Interactions of the FHRs with pentraxins resulted in enhanced activation of both the classical and the alternative complement pathways on dead cells when exposed to human serum. Altogether, our results demonstrate that FHR-1 and FHR-5 are competitive inhibitors of FH on DNA; moreover, FHR-pentraxin interactions promote opsonization of dead cells.
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Affiliation(s)
- Éva Kárpáti
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Alexandra Papp
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Andrea E Schneider
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dávid Hajnal
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Marcell Cserhalmi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Ádám I Csincsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
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38
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Wu Q, Cao F, Tao J, Li X, Zheng SG, Pan HF. Pentraxin 3: A promising therapeutic target for autoimmune diseases. Autoimmun Rev 2020; 19:102584. [PMID: 32534154 DOI: 10.1016/j.autrev.2020.102584] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/15/2022]
Abstract
Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern recognition molecule that exerts a pivotal role in innate immune response and inflammation, as well as in tissue damage and remodeling. Recently, emerging evidence has revealed that PTX3 is involved in the occurrence and development of various autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), systemic sclerosis (SSc), inflammatory bowel disease (IBD), multiple sclerosis (MS) and psoriasis, etc. In this review, we have succinctly summarized the complex immunological functions of PTX3 and mostly focused on recent findings of the pleiotropic activities played by PTX3 in the pathogenesis of autoimmune diseases, aiming at hopefully offering possible future therapeutic alternatives.
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Affiliation(s)
- Qian Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Anhui Province Laboratory of Inflammation and Immune Mediated Diseases, 81 Meishan Road, Hefei, Anhui, China
| | - Fan Cao
- Department of Clinical Medicine, The second School of Clinical Medicine, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China
| | - Jinhui Tao
- Department of Rheumatology and Immunology, The First Affiliated Hospital, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiaomei Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital, University of Science and Technology of China, Hefei, Anhui, China
| | - Song Guo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA.
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, China; Anhui Province Laboratory of Inflammation and Immune Mediated Diseases, 81 Meishan Road, Hefei, Anhui, China.
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39
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Parente R, Doni A, Bottazzi B, Garlanda C, Inforzato A. The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins. FEBS Lett 2020; 594:2480-2501. [PMID: 31994174 DOI: 10.1002/1873-3468.13744] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/19/2019] [Accepted: 01/16/2020] [Indexed: 12/13/2022]
Abstract
Aspergillosis is a life-threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host-pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement-dependent effector with protective functions against A. fumigatus. Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.
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Affiliation(s)
- Raffaella Parente
- Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy
| | - Andrea Doni
- Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy
| | - Barbara Bottazzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy
| | - Cecilia Garlanda
- Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Antonio Inforzato
- Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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40
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Kang Y, Yu Y, Lu L. The Role of Pentraxin 3 in Aspergillosis: Reality and Prospects. MYCOBIOLOGY 2020; 48:1-8. [PMID: 32158600 PMCID: PMC7048186 DOI: 10.1080/12298093.2020.1722576] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 01/10/2020] [Accepted: 01/23/2020] [Indexed: 02/08/2023]
Abstract
Pentraxin 3 (PTX3) is a soluble pattern recognition receptor (PRR), which is produced by several kinds of cells, such as neutrophils, dendritic cells, macrophages, and epithelial cells. PTX3 is known to play an important protective effect against Aspergillus. Genetic linkage in gene-targeted mice and human PTX3 plays a non-redundant role in the immune protection against specific pathogens, especially Aspergillus. Recent studies have shown that the polymorphism of PTX3 is associated with increased susceptibility to invasive aspergillosis (IA). In this review, we provide an overview of these studies that underline the potential of PTX3 in diagnosis and therapy of IA.
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Affiliation(s)
- Yuening Kang
- Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuetian Yu
- Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liangjing Lu
- Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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41
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Westman J, Grinstein S, Marques PE. Phagocytosis of Necrotic Debris at Sites of Injury and Inflammation. Front Immunol 2020; 10:3030. [PMID: 31998312 PMCID: PMC6962235 DOI: 10.3389/fimmu.2019.03030] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/10/2019] [Indexed: 12/20/2022] Open
Abstract
Clearance of cellular debris is required to maintain the homeostasis of multicellular organisms. It is intrinsic to processes such as tissue growth and remodeling, regeneration and resolution of injury and inflammation. Most of the removal of effete and damaged cells is performed by macrophages and neutrophils through phagocytosis, a complex phenomenon involving ingestion and degradation of the disposable particles. The study of the clearance of cellular debris has been strongly biased toward the removal of apoptotic bodies; as a result, the mechanisms underlying the removal of necrotic cells have remained relatively unexplored. Here, we will review the incipient but growing knowledge of the phagocytosis of necrotic debris, from their recognition and engagement to their internalization and disposal. Critical insights into these events were gained recently through the development of new in vitro and in vivo models, along with advances in live-cell and intravital microscopy. This review addresses the classes of "find-me" and "eat-me" signals presented by necrotic cells and their cognate receptors in phagocytes, which in most cases differ from the extensively characterized counterparts in apoptotic cell engulfment. The roles of damage-associated molecular patterns, chemokines, lipid mediators, and complement components in recruiting and activating phagocytes are reviewed. Lastly, the physiological importance of necrotic cell removal is emphasized, highlighting the key role of impaired debris clearance in autoimmunity.
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Affiliation(s)
- Johannes Westman
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
| | - Sergio Grinstein
- Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.,Department of Biochemistry, University of Toronto, Toronto, ON, Canada.,Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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Regulation of regulators: Role of the complement factor H-related proteins. Semin Immunol 2019; 45:101341. [PMID: 31757608 DOI: 10.1016/j.smim.2019.101341] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/07/2019] [Accepted: 10/24/2019] [Indexed: 01/15/2023]
Abstract
The complement system, while being an essential and very efficient effector component of innate immunity, may cause damage to the host and result in various inflammatory, autoimmune and infectious diseases or cancer, when it is improperly activated or regulated. Factor H is a serum glycoprotein and the main regulator of the activity of the alternative complement pathway. Factor H, together with its splice variant factor H-like protein 1 (FHL-1), inhibits complement activation at the level of the central complement component C3 and beyond. In humans, there are also five factor H-related (FHR) proteins, whose function is poorly characterized. While data indicate complement inhibiting activity for some of the FHRs, there is increasing evidence that FHRs have an opposite role compared with factor H and FHL-1, namely, they enhance complement activation directly and also by competing with the regulators FH and FHL-1. This review summarizes the current stand and recent data on the roles of factor H family proteins in health and disease, with focus on the function of FHR proteins.
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Chen C, Lv Y, Hu C, Xu XF, Zhang RQ, Xiao K, Ma Y, Gao LP, Li JL, Shi Q, Wang J, Shi Q, Dong XP. Alternative complement pathway is activated in the brains of scrapie-infected rodents. Med Microbiol Immunol 2019; 209:81-94. [PMID: 31720785 DOI: 10.1007/s00430-019-00641-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 10/30/2019] [Indexed: 11/28/2022]
Abstract
Activation of complement system in central nervous system (CNS) of the patients suffering from prion diseases or animal models infected with prion agents experimentally is reported repeatedly, but which pathways are involved in the complement system during prion infection is not well documented. Here, we evaluated the level of complement factor B (CFB), which is the key factor that triggers alterative pathway (AP) of complement in the brain tissues of scrapie-infected mice with various methodologies. We found that the levels of mRNA and protein of CFB significantly increased in the brain tissues of scrapie-infected mice. Morphologically, the increased CFB-specific signal overlapped with the elevated C3 signal in brain sections of scrapie-infected mice, meanwhile overlapped with damaged neurons and activated microglia, but not with the proliferative astrocytes. Additionally, the level of complement factor P (CFP), the key positive regulator of AP, also increased remarkably in the brain tissues of infected mice. The transcriptional levels of CD55 and CD46, two negative regulators of AP, decreased without significance in brain tissues of scrapie-infected mice at the terminal stage. However, the mRNA and protein levels of CFH, another negative regulator of AP, increased. Through the dynamic analyses of the expressions of CFB, CFP, and CFH in brain sections of 139A-infected mice, which were collected at different time-points during incubation period, illustrated time-dependent increase levels of each factor during the incubation period of scrapie infection. Taken together, our data here demonstrate that the AP of complement cascade is activated in the CNS microenvironment during prion infection.
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Affiliation(s)
- Cao Chen
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China.,Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People's Republic of China
| | - Yan Lv
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Chao Hu
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Xiao-Feng Xu
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Ren-Qing Zhang
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Kang Xiao
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Yue Ma
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Li-Ping Gao
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Jian-Le Li
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Qiang Shi
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Jing Wang
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Qi Shi
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Xiao-Ping Dong
- State Key Laboratory for Infectious Disease Prevention and Control, NHC Key Laboratory of Medical Virology and Viral Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China. .,Center of Global Public Health, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China. .,Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People's Republic of China. .,China Academy of Chinese Medical Sciences, Dongzhimeinei, South Rd 16, Beijing, 100700, China.
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Wu Q, Guan SY, Dan YL, Zhao CN, Mao YM, Liu LN, Li XM, Wang DG, Pan HF. Circulating pentraxin-3 levels in patients with systemic lupus erythematosus: a meta-analysis. Biomark Med 2019; 13:1417-1427. [PMID: 31599644 DOI: 10.2217/bmm-2019-0161] [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] [Indexed: 12/29/2022] Open
Abstract
Aim: An existing meta-analysis have investigated the PTX3 levels in systemic lupus erythematosus (SLE) patients, but the number of studies has increased since 2015. We performed an updated meta-analysis to derive a more accurate estimation. Methods: The related literature was systematically searched in PubMed, Embase and The Cochrane Library database (up to 28 February, 2019). Results: SLE patients had significantly higher PTX3 levels than controls (pooled SMD = 0.48; 95% CI: 0.11-0.84). Subgroup analyses indicated SLE patients from non-Caucasian population, with age ≥45 years, SLE disease activity index (SLEDAI) ≥10 and plasma samples had higher PTX3 levels. Conclusion: Circulating PTX3 levels are increased in SLE patients, and affected by age, ethnicity, SLEDAI and sample type.
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Affiliation(s)
- Qian Wu
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Shi-Yang Guan
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Yi-Lin Dan
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Chan-Na Zhao
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Yan-Mei Mao
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Li-Na Liu
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
| | - Xiao-Mei Li
- Department of Rheumatology & Immunology, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui, PR China
| | - De-Guang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, PR China
| | - Hai-Feng Pan
- Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, PR China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, 81 Meishan Road, Hefei, Anhui, PR China
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Wu XY, Li KT, Yang HX, Yang B, Lu X, Zhao LD, Fei YY, Chen H, Wang L, Li J, Peng LY, Zheng WJ, Hou Y, Jiang Y, Shi Q, Zhang W, Zhang FC, Zhang JM, Huang B, He W, Zhang X. Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis. J Autoimmun 2019; 106:102336. [PMID: 31601476 DOI: 10.1016/j.jaut.2019.102336] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/23/2019] [Accepted: 09/23/2019] [Indexed: 11/27/2022]
Abstract
Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1β and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
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Affiliation(s)
- Xun-Yao Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Ke-Tian Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Hua-Xia Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Bo Yang
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xin Lu
- Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Li-Dan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Yun-Yun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Jing Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Ling-Yi Peng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Wen-Jie Zheng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Yong Hou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Ying Jiang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Qun Shi
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Feng-Chun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Jian-Min Zhang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China
| | - Bo Huang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China
| | - Wei He
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China; Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Chen SF, Wang FM, Li ZY, Yu F, Chen M, Zhao MH. Myeloperoxidase influences the complement regulatory activity of complement factor H. Rheumatology (Oxford) 2019; 57:2213-2224. [PMID: 29471467 DOI: 10.1093/rheumatology/kex529] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Indexed: 11/12/2022] Open
Abstract
Objective The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH. Methods Detection of FH and MPO on neutrophil extracellular traps (NETs) induced by serum from AAV patients and in kidney biopsies of AAV patients was performed by immunostaining. In vitro binding between MPO and FH was examined by ELISA and surface plasmon resonance. The influence of MPO on the complement regulatory activity of FH was further assessed. Results FH deposited and co-localized with MPO in NETs. In kidney biopsies from AAV patients, MPO was closely adjacent to FH in glomerular capillaries. We demonstrated that MPO binds to FH with an apparent nanomolar affinity and identified short consensus repeats 1-4 of FH as the major binding sites. In terms of functional analysis, MPO inhibited the interaction between FH and C3b and the decay-accelerating activity of FH. The fluid phase and surface cofactor activities of FH upon C3b inactivation were inhibited by MPO. Conclusion Our findings indicate that MPO binds to FH and influences the complement regulatory activity of FH. MPO-FH interaction may participate in the pathogenesis of AAV by contributing to activation of the alternative complement pathway.
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Affiliation(s)
- Su-Fang Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Feng-Mei Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Zhi-Ying Li
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Feng Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Beijing, China
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Haapasalo K, Meri S. Regulation of the Complement System by Pentraxins. Front Immunol 2019; 10:1750. [PMID: 31428091 PMCID: PMC6688104 DOI: 10.3389/fimmu.2019.01750] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 07/10/2019] [Indexed: 01/09/2023] Open
Abstract
The functions of pentraxins, like C-reactive protein (CRP), serum amyloid protein P (SAP) and pentraxin-3 (PTX3), are to coordinate spatially and temporally targeted clearance of injured tissue components, to protect against infections and to regulate related inflammation together with the complement system. For this, pentraxins have a dual relationship with the complement system. Initially, after a focused binding to their targets, e.g., exposed phospholipids or cholesterol in the injured tissue area, or microbial components, the pentraxins activate complement by binding its first component C1q. However, the emerging inflammation needs to be limited to the target area. Therefore, pentraxins inhibit complement at the C3b stage to prevent excessive damage. The complement inhibitory functions of pentraxins are based on their ability to interact with complement inhibitors C4bp or factor H (FH). C4bp binds to SAP, while FH binds to both CRP and PTX3. FH promotes opsonophagocytosis through inactivation of C3b to iC3b, and inhibits AP activity thus preventing formation of the C5a anaphylatoxin and the complement membrane attack complex (MAC). Monitoring CRP levels gives important clinical information about the extent of tissue damage and severity of infections. CRP is a valuable marker for distinguishing bacterial infections from viral infections. Disturbances in the functions and interactions of pentraxins and complement are also involved in a number of human diseases. This review will summarize what is currently known about the FH family proteins and pentraxins that interact with FH. Furthermore, we will discuss diseases, where interactions between these molecules may play a role.
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Affiliation(s)
- Karita Haapasalo
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.,HUSLAB, Helsinki University Hospital, Helsinki, Finland.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Wyskida K, Franik G, Pohl N, Markuszewski L, Owczarek A, Madej P, Chudek J, Olszanecka-Glinianowicz M. Pentraxin 3 as a marker of endothelial dysfunction in young women with polycystic ovary syndrome (PCOS). Scand J Clin Lab Invest 2019; 79:419-423. [PMID: 31282210 DOI: 10.1080/00365513.2019.1637535] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
One of the consequences of polycystic ovary syndrome (PCOS) is an increased risk of early development of cardiovascular diseases. Pentraxin-3 (PTX-3) is a new potential marker of endothelial dysfunction. The aim of the study was to assess PTX3 and other markers of endothelial dysfunction in PCOS women. The study enrolled 99 stable body mass PCOS women (17 normal weight, 21 overweight and 61 obese). Anthropometric measurements and serum/plasma levels of glucose, insulin, lipids, estradiol, testosterone, sex hormone binding globulin, 17-OH progesterone, free androgen index, pentraxin-3 (PTX3), soluble intercellular (sICAM-1) and vascular cell adhesion molecule 1 (sVCAM-1), endothelin-1 and total nitric oxide metabolites (tNO) concentrations were assessed. Groups were divided into tercile-subgroups according to PTX3 serum levels. Serum PTX3 tercile-subgroups significantly differed in respect to tNO, endothelin-1 and sVCAM-1, but not sICAM-1. The levels of tNO, endothelin-1 and sVCAM-1 were significantly decreased in the subgroup with the lowest PTX3 levels compared to both middle (tNO and endothelin 1) and upper tercile subgroups (all of them). There were significant positive correlations between log10(PTX3) and log10(tNO) (r = 0.34, p < .001), log10(endothelin-1) (r = 0.41, p < .001) as well as sVCAM-1 levels (r = 0.22, p < .05). Circulating PTX-3 levels seem to be a marker of endothelial dysfunction in PCOS women.
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Affiliation(s)
- Katarzyna Wyskida
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical Faculty in Katowice, Medical University of Silesia , Katowice , Poland
| | - Grzegorz Franik
- Department of Gynecological Endocrinology, Medical University of Silesia , Katowice , Poland
| | - Natalia Pohl
- Department of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia , Katowice , Poland
| | - Leszek Markuszewski
- Clinic of Endocrinology and Metabolic Diseases, Institute of Polish Mother's Health Center , Lodz , Poland
| | - Aleksander Owczarek
- Department of Statistics, Department of Instrumental Analysis, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia , Katowice , Poland
| | - Paweł Madej
- Department of Gynecological Endocrinology, Medical University of Silesia , Katowice , Poland
| | - Jerzy Chudek
- Pathophysiology Unit, Department of Pathophysiology, Medical Faculty in Katowice, Medical University of Silesia , Katowice , Poland.,Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia , Katowice , Poland
| | - Magdalena Olszanecka-Glinianowicz
- Health Promotion and Obesity Management Unit, Department of Pathophysiology, Medical Faculty in Katowice, Medical University of Silesia , Katowice , Poland
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Yang ZH, Dang YQ, Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J Gastroenterol 2019; 25:2863-2877. [PMID: 31249445 PMCID: PMC6589733 DOI: 10.3748/wjg.v25.i23.2863] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.
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Affiliation(s)
- Zhen-Hua Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Digestive Endoscopy Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Qi Dang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Ristagno G, Fumagalli F, Bottazzi B, Mantovani A, Olivari D, Novelli D, Latini R. Pentraxin 3 in Cardiovascular Disease. Front Immunol 2019; 10:823. [PMID: 31057548 PMCID: PMC6481278 DOI: 10.3389/fimmu.2019.00823] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/28/2019] [Indexed: 12/30/2022] Open
Abstract
The long pentraxin PTX3 is a member of the pentraxin family produced locally by stromal and myeloid cells in response to proinflammatory signals and microbial moieties. The prototype of the pentraxin family is C reactive protein (CRP), a widely-used biomarker in human pathologies with an inflammatory or infectious origin. Data so far describe PTX3 as a multifunctional protein acting as a functional ancestor of antibodies and playing a regulatory role in inflammation. Cardiovascular disease (CVD) is a leading cause of mortality worldwide, and inflammation is crucial in promoting it. Data from animal models indicate that PTX3 can have cardioprotective and atheroprotective roles regulating inflammation. PTX3 has been investigated in several clinical settings as possible biomarker of CVD. Data collected so far indicate that PTX3 plasma levels rise rapidly in acute myocardial infarction, heart failure and cardiac arrest, reflecting the extent of tissue damage and predicting the risk of mortality.
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Affiliation(s)
- Giuseppe Ristagno
- Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy
| | - Francesca Fumagalli
- Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy
| | | | - Alberto Mantovani
- Humanitas Clinical and Research Center-IRCCS, Milan, Italy.,Humanitas University, Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Davide Olivari
- Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy
| | - Deborah Novelli
- Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy
| | - Roberto Latini
- Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy
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