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Kiss O, Bahri R, Watson REB, Chike C, Langton AK, Newton VL, Bell M, Griffiths CEM, Bulfone-Paus S, Pilkington SM. The impact of irritant challenge on the skin barrier and myeloid-resident immune cells in women who are postmenopausal is modulated by hormone replacement therapy. Br J Dermatol 2024; 191:746-759. [PMID: 38819239 DOI: 10.1093/bjd/ljae226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 05/18/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. OBJECTIVES To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge. METHODS Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. RESULTS Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge. CONCLUSIONS Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.
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Affiliation(s)
- Orsolya Kiss
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Rajia Bahri
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation and Manchester Collaborative Centre for Inflammation Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Rachel E B Watson
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), National Skin Centre and Skin Research Institute of Singapore (SRIS), Republic of Singapore
| | - Chidera Chike
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Abigail K Langton
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Mike Bell
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | - Christopher E M Griffiths
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Department of Dermatology, King's College Hospital NHS Foundation Trust, King's College London, London, UK
| | - Silvia Bulfone-Paus
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation and Manchester Collaborative Centre for Inflammation Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Suzanne M Pilkington
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Rojekar S, Gholap AD, Togre N, Bhoj P, Haeck C, Hatvate N, Singh N, Vitore J, Dhoble S, Kashid S, Patravale V. Current status of mannose receptor-targeted drug delivery for improved anti-HIV therapy. J Control Release 2024; 372:494-521. [PMID: 38849091 DOI: 10.1016/j.jconrel.2024.06.002] [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: 03/12/2024] [Revised: 05/22/2024] [Accepted: 06/01/2024] [Indexed: 06/09/2024]
Abstract
In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors, which are primarily found on macrophages and dendritic cells, offer promising targets for drug delivery due to their involvement in HIV pathogenesis. This review article comprehensively evaluates recent drug delivery system advancements targeting the mannose receptor. We have systematically described recent developments in creating and utilizing drug delivery platforms, including nanoparticles, liposomes, micelles, noisomes, dendrimers, and other nanocarrier systems targeted at the mannose receptor. These strategies aim to enhance drug delivery specificity, bioavailability, and therapeutic efficacy while decreasing off-target effects and systemic toxicity. Furthermore, the article delves into how mannose receptors and HIV interact, highlighting the potential for exploiting this interaction to enhance drug delivery to infected cells. The review covers essential topics, such as the rational design of nanocarriers for mannose receptor recognition, the impact of physicochemical properties on drug delivery performance, and how targeted delivery affects the pharmacokinetics and pharmacodynamics of anti-HIV agents. The challenges of these novel strategies, including immunogenicity, stability, and scalability, and future research directions in this rapidly growing area are discussed. The knowledge synthesis presented in this review underscores the potential of mannose receptor-based targeted drug delivery as a promising avenue for advancing HIV treatment. By leveraging the unique properties of mannose receptors, researchers can design drug delivery systems that cater to individual needs, overcome existing limitations, and create more effective and patient-friendly treatments in the ongoing fight against HIV/AIDS.
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Affiliation(s)
- Satish Rojekar
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Amol D Gholap
- Department of Pharmaceutics, St. John Institute of Pharmacy and Research, Palghar 401404, Maharashtra, India
| | - Namdev Togre
- Department of Pathology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
| | - Priyanka Bhoj
- Department of Pathology, Lewis Katz School of Medicine at Temple University, Philadelphia, USA
| | - Clement Haeck
- Population Council, , Center for Biomedical Research, 1230 York Avenue, New York, NY 10065, USA
| | - Navnath Hatvate
- Institute of Chemical Technology, Mumbai, Marathwada Campus, Jalna 431203, India
| | - Nidhi Singh
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Kolkata 700054, India
| | - Jyotsna Vitore
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Gujarat 382355, India
| | - Sagar Dhoble
- Department of Pharmacology and Toxicology, R. K. Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | - Snehal Kashid
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Ahmedabad (NIPER-A), Gujarat 382355, India
| | - Vandana Patravale
- Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, India.
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Quartey BC, Sapudom J, ElGindi M, Alatoom A, Teo J. Matrix-Bound Hyaluronan Molecular Weight as a Regulator of Dendritic Cell Immune Potency. Adv Healthc Mater 2024; 13:e2303125. [PMID: 38104242 DOI: 10.1002/adhm.202303125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 12/07/2023] [Indexed: 12/19/2023]
Abstract
Hyaluronic acid (HA) is a glycosaminoglycan in the extracellular matrix with immunoregulatory properties depending on its molecular weight (MW). However, the impact of matrix-bound HA on dendritic cells (DCs) remains unclear due to varying distribution of HA MW under different physiological conditions. To investigate DCs in defined biosystems, 3D collagen matrices modified with HA of specific MW with similar microstructure and HA levels are used. It is found that HA MW influences cytokine binding to matrix, suggesting modulation of cytokine availability by the different HA MWs. These studies on DC immune potency reveal that low MW HA (8-15 kDa) enhances immature DC differentiation and antigen uptake, while medium (MMW-HA; 500-750 kDa) and high MW HA (HMW-HA; 1250-1500 kDa) increase cytokine secretion in mature DCs. The effect on DC phenotype and cytokine secretion by different MWs of HA is independent of CD44. However, blocking the CD44 receptor reveals its potential role in regulating acute inflammation through increased secretion of CCL2, CXCL8, and IL-6. Additionally, MMW- and HMW-HA matrices reduce migratory capacity of DCs, dependent on CD44. Overall, these findings provide insights into MW-dependent effects of matrix-bound HA on DCs, opening avenues for the design of DC-modulating materials to enhance DC-based therapy.
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Affiliation(s)
- Brian Chesney Quartey
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi, 129188, UAE
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 6 MetroTech Center, Brooklyn, NY, 11201, USA
| | - Jiranuwat Sapudom
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi, 129188, UAE
| | - Mei ElGindi
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi, 129188, UAE
| | - Aseel Alatoom
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi, 129188, UAE
- Department of Mechanical Engineering, Tandon School of Engineering, New York University, 6 MetroTech Center, Brooklyn, 11201, USA
| | - Jeremy Teo
- Laboratory for Immuno Bioengineering Research and Applications, Division of Engineering, New York University Abu Dhabi, Abu Dhabi, 129188, UAE
- Department of Mechanical Engineering, Tandon School of Engineering, New York University, 6 MetroTech Center, Brooklyn, 11201, USA
- Department of Biomedical Engineering, Tandon School of Engineering, New York University, 6 MetroTech Center, Brooklyn, NY, 11201, USA
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Paurević M, Šrajer Gajdošik M, Ribić R. Mannose Ligands for Mannose Receptor Targeting. Int J Mol Sci 2024; 25:1370. [PMID: 38338648 PMCID: PMC10855088 DOI: 10.3390/ijms25031370] [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: 12/14/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
The mannose receptor (MR, CD 206) is an endocytic receptor primarily expressed by macrophages and dendritic cells, which plays a critical role in both endocytosis and antigen processing and presentation. MR carbohydrate recognition domains (CRDs) exhibit a high binding affinity for branched and linear oligosaccharides. Furthermore, multivalent mannose presentation on the various templates like peptides, proteins, polymers, micelles, and dendrimers was proven to be a valuable approach for the selective and efficient delivery of various therapeutically active agents to MR. This review provides a detailed account of the most relevant and recent aspects of the synthesis and application of mannosylated bioactive formulations for MR-mediated delivery in treatments of cancer and other infectious diseases. It further highlights recent findings related to the necessary structural features of the mannose-containing ligands for successful binding to the MR.
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Affiliation(s)
- Marija Paurević
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia; (M.P.); (M.Š.G.)
| | - Martina Šrajer Gajdošik
- Department of Chemistry, Josip Juraj Strossmayer University of Osijek, Cara Hadrijana 8/A, HR-31000 Osijek, Croatia; (M.P.); (M.Š.G.)
| | - Rosana Ribić
- Department of Nursing, University Center Varaždin, University North, Jurja Križanića 31b, HR-42000 Varaždin, Croatia
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van der Zande HJP, Nitsche D, Schlautmann L, Guigas B, Burgdorf S. The Mannose Receptor: From Endocytic Receptor and Biomarker to Regulator of (Meta)Inflammation. Front Immunol 2021; 12:765034. [PMID: 34721436 PMCID: PMC8551360 DOI: 10.3389/fimmu.2021.765034] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/27/2021] [Indexed: 01/27/2023] Open
Abstract
The mannose receptor is a member of the C-type lectin (CLEC) family, which can bind and internalize a variety of endogenous and pathogen-associated ligands. Because of these properties, its role in endocytosis as well as antigen processing and presentation has been studied intensively. Recently, it became clear that the mannose receptor can directly influence the activation of various immune cells. Cell-bound mannose receptor expressed by antigen-presenting cells was indeed shown to drive activated T cells towards a tolerogenic phenotype. On the other hand, serum concentrations of a soluble form of the mannose receptor have been reported to be increased in patients suffering from a variety of inflammatory diseases and to correlate with severity of disease. Interestingly, we recently demonstrated that the soluble mannose receptor directly promotes macrophage proinflammatory activation and trigger metaflammation. In this review, we highlight the role of the mannose receptor and other CLECs in regulating the activation of immune cells and in shaping inflammatory responses.
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Affiliation(s)
| | - Dominik Nitsche
- Cellular Immunology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Laura Schlautmann
- Cellular Immunology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Sven Burgdorf
- Cellular Immunology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
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Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation. Proc Natl Acad Sci U S A 2021; 118:2103304118. [PMID: 34326259 DOI: 10.1073/pnas.2103304118] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.
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Wang F, Ullah A, Fan X, Xu Z, Zong R, Wang X, Chen G. Delivery of nanoparticle antigens to antigen-presenting cells: from extracellular specific targeting to intracellular responsive presentation. J Control Release 2021; 333:107-128. [PMID: 33774119 DOI: 10.1016/j.jconrel.2021.03.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 02/05/2023]
Abstract
An appropriate delivery system can improve the immune effects of antigens against various infections or tumors. Antigen-presenting cells (APCs) are specialized to capture and process antigens in vivo, which link the innate and adaptive immune responses. Functionalization of vaccine delivery systems with targeting moieties to APCs is a promising strategy for provoking potent immune responses. Additionally, the internalization and intracellular distribution of antigens are closely related to the initiation of downstream immune responses. With a deeper understanding of the intracellular microenvironment and the mechanisms of antigen presentation, vehicles designed to respond to endogenous and external stimuli can modulate antigen processing and presentation pathways, which are critical to the types of immune response. Here, an overview of extracellular targeting delivery of antigens to APCs and intracellular stimulus-responsiveness strategies is provided, which might be helpful for the rational design of vaccine delivery systems.
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Affiliation(s)
- Fei Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Aftab Ullah
- Shantou University Medical College, Shantou 515041, China
| | - Xuelian Fan
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Zhou Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Rongling Zong
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Xuewen Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Gang Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China.
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Nielsen MC, Hvidbjerg Gantzel R, Clària J, Trebicka J, Møller HJ, Grønbæk H. Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure. Cells 2020; 9:cells9051175. [PMID: 32397365 PMCID: PMC7290463 DOI: 10.3390/cells9051175] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the existing literature on sCD163 and sCD206 function and shedding, and potential as biomarkers in acute and chronic liver diseases with a particular focus on Acute-on-Chronic Liver Failure (ACLF). In multiple studies sCD163 and sCD206 are elevated in relation to liver disease severity and established as reliable predictors of morbidity and mortality. However, differences in expression- and shedding-stimuli for CD163 and CD206 may explain dissimilarities in prognostic utility in patients with acute decompensation of cirrhosis and ACLF.
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Affiliation(s)
- Marlene Christina Nielsen
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.C.N.); (H.J.M.)
| | - Rasmus Hvidbjerg Gantzel
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, Denmark;
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain; (J.C.); (J.T.)
- Department of Biochemistry and Molecular Genetics, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain
| | - Jonel Trebicka
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF), 08021 Barcelona, Spain; (J.C.); (J.T.)
- Translational Hepatology, Department of Internal Medicine I, Goethe University Frankfurt, 60323 Frankfurt, Germany
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, 8200 Aarhus N, Denmark; (M.C.N.); (H.J.M.)
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, Denmark;
- Correspondence: ; Tel.: +45-21-67-92-81
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Li TP, Guan SH, Wang Q, Chen LW, Yang K, Zhang H. Soluble mannose receptor as a predictor of prognosis of hepatitis B virus-related acute-on-chronic liver failure. World J Gastroenterol 2019; 25:5667-5675. [PMID: 31602166 PMCID: PMC6785521 DOI: 10.3748/wjg.v25.i37.5667] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/21/2019] [Accepted: 09/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a syndrome with a high short-term mortality rate, and it is crucial to identify those patients at a high mortality risk clinically.
AIM To investigate the clinical value of soluble mannose receptor (sMR) in predicting the 90-day mortality of HBV-ACLF patients.
METHODS A total of 43 patients were diagnosed with HBV-ACLF between October 2017 and October 2018 at the Second Hospital of Anhui Medical University, and all of them were enrolled in this retrospective study. Their serum sMR levels were determined using an enzyme-linked immunosorbent assay. Demographic and clinical data, including gender, age, albumin level, total bilirubin (TBIL) level, international normalized ratio, HBV-DNA level, HBV serological markers, procalcitonin level, interleukin-6 level, and model for end-stage liver disease (MELD) score were accessed at the time of diagnosis of HBV-ACLF. A multivariate logistic regression analysis was used to analyze the independent risk factors for mortality.
RESULTS Serum sMR level was significantly increased in HBV-ACLF patients compared with chronic hepatitis B patients and healthy controls (P < 0.01). When compared with surviving patients, it was higher in those patients who succumbed to HBV-ACLF (P < 0.05). Serum sMR level was positively correlated with MELD score (rs = 0.533, P = 0.001), HBV-DNA level (rs = 0.497, P = 0.022), and TBIL level (rs = 0.894, P < 0.001). Serum sMR level (odds ratio = 1.007, 95% confidence interval: 1.004–1.012, P = 0.001) was an independent risk factor for the 90-day mortality in the HBV-ACLF cases. The patients with HBV-ACLF were stratified into two groups in accordance with their serum sMR levels at the baseline (low risk: < 99.84 pg/mL and high risk: ≥ 99.84 pg/mL). The 90-day mortality rates were 27.3% in the low-risk group and 87.5% in the high-risk group. Furthermore, sMR level apparently improved the performance of MELD score for predicting the prognosis of patients with HBV-ACLF.
CONCLUSION Serum sMR level may be a predictor of the prognosis of HBV-ACLF patients.
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Affiliation(s)
- Tai-Ping Li
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Shi-He Guan
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Qin Wang
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Li-Wen Chen
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Kai Yang
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
| | - Hao Zhang
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
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Nielsen MC, Andersen MN, Rittig N, Rødgaard-Hansen S, Grønbaek H, Moestrup SK, Møller HJ, Etzerodt A. The macrophage-related biomarkers sCD163 and sCD206 are released by different shedding mechanisms. J Leukoc Biol 2019; 106:1129-1138. [PMID: 31242338 DOI: 10.1002/jlb.3a1218-500r] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 05/30/2019] [Accepted: 06/17/2019] [Indexed: 01/05/2023] Open
Abstract
The hemoglobin receptor CD163 and the mannose receptor CD206 are both expressed on the surface of human macrophages. Upon inflammatory activation, the receptors are shed from the macrophage surface generating soluble products. The plasma concentration of both soluble CD163 (sCD163) and soluble CD206 (sCD206) are increased in several diseases, including inflammatory conditions and cancer. Here, we show that in contrast to CD163, LPS-mediated shedding of CD206 in humans is slow and a result of indirect signaling. Although both sCD163 and sCD206 were increased in response to LPS stimulation in vivo, only CD163 was shed from LPS-stimulated macrophages in vitro. Although both sCD163 and sCD206 were released from cultured macrophages stimulated with zymosan and PMA, shedding of CD206 was generally slower and less efficient and not reduced by inhibitors against the major protease classes. These data indicate that CD163 and CD206 are shed from the macrophages by very different mechanisms potentially involving distinctive inflammatory processes.
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Affiliation(s)
| | - Morten Nørgaard Andersen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Nikolaj Rittig
- Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Søren Kragh Moestrup
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark
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Marie Relster M, Gaini S, Møller HJ, Johansen IS, Pedersen C. The macrophage activation marker sMR as a diagnostic and prognostic marker in patients with acute infectious disease with or without sepsis. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:180-186. [PMID: 29383956 DOI: 10.1080/00365513.2018.1431841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Sepsis is a leading cause of mortality. This study aims to assess the utility of the soluble mannose receptor (sMR) as a biomarker of sepsis and mortality in patients hospitalized with suspected infection. Using an in-house ELISA assay the concentration of sMR was analyzed in the serum of patients from three prospective studies. Using Sepsis-3 guidelines, patients were stratified as no infection (NI, n = 68), verified infection without sepsis (NSEP, n = 133) and verified infection with sepsis (SEP, n = 190). Adverse outcome was assessed as death before 28 days. We show that the sensitivity of sMR to predict mortality [area under curve (AUC) = 0.77] exceeded the sensitivity of procalcitonin (PCT, AUC = 0.63), C-reactive protein (CRP, AUC = 0.61) and the macrophage soluble receptor, CD163 (sCD163, AUC = 0.74), while it was less accurate to predict diagnosis of sepsis [AUC(sMR) = 0.69 vs. AUC(PCT) = 0.79, AUC(CRP) = 0.71 and AUC(sCD163) = 0.66]. Median sMR was significantly higher in the group with SEP (0.55 mg/L), compared with the groups without sepsis (NI and NSEP) (0.39 mg/L, p < .0001), and among those who died compared to those who survived (0.89 mg/L vs. 0.44 mg/L, p < .0001). Our results, and the current literature, support further evaluation of sMR as a biomarker of sepsis and mortality among patients hospitalized with suspected infection.
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Affiliation(s)
- Mette Marie Relster
- a Department Infectious Diseases , Odense University Hospital , Odense , Denmark
| | - Shahin Gaini
- a Department Infectious Diseases , Odense University Hospital , Odense , Denmark.,b Medical Department, Infectious Diseases Division , National Hospital Faroe Islands , Torshavn , The Faroe Islands.,c Centre of Health Research , University of the Faroe Islands , Torshavn , The Faroe Islands
| | - Holger Jon Møller
- d Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus N , Denmark
| | | | - Court Pedersen
- a Department Infectious Diseases , Odense University Hospital , Odense , Denmark
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12
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The soluble mannose receptor (sMR) is elevated in alcoholic liver disease and associated with disease severity, portal hypertension, and mortality in cirrhosis patients. PLoS One 2017; 12:e0189345. [PMID: 29236785 PMCID: PMC5728513 DOI: 10.1371/journal.pone.0189345] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/24/2017] [Indexed: 12/13/2022] Open
Abstract
Background and aims Hepatic macrophages (Kupffer cells) are involved in the immunopathology of alcoholic liver disease (ALD). The mannose receptor (MR, CD206), expressed primarily by macrophages, mediates endocytosis, antigen presentation and T-cell activation. A soluble form, sMR, has recently been identified in humans. We aimed to study plasma sMR levels and its correlation with disease severity and survival in ALD patients. Methods We included 50 patients with alcoholic hepatitis (AH), 68 alcoholic cirrhosis (AC) patients (Child-Pugh A (23), B (24), C (21)), and 21 healthy controls (HC). Liver status was described by the Glasgow Alcoholic Hepatitis Score (GAHS), Child-Pugh (CP) and MELD-scores, and in AC patients the hepatic venous pressure gradient (HVPG) was measured by liver vein catheterisation. We used Kaplan-Meier statistics for short-term survival (84-days) in AH patients and long-term (4 years) in AC patients. We measured plasma sMR by ELISA. Results Median sMR concentrations were significantly elevated in AH 1.32(IQR:0.69) and AC 0.46(0.5) compared to HC 0.2(0.06) mg/L; p<0.001 and increased in a stepwise manner with the CP-score (p<0.001). In AC sMR predicted portal hypertension (HVPG ≥10 mmHg) with an area under the Receiver Operator Characteristics curve of 0.86 and a high sMR cut-off (>0.43 mg/l) was associated with increased mortality (p = 0.005). Conclusion The soluble mannose receptor is elevated in alcoholic liver disease, especially in patients with AH. Its blood level predicts portal hypertension and long-term mortality in AC patients.
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13
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Yamamoto-Oka H, Mizuguchi S, Toda M, Minamiyama Y, Takemura S, Shibata T, Cepinskas G, Nishiyama N. Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro. Inflammopharmacology 2017; 26:435-445. [PMID: 28674739 DOI: 10.1007/s10787-017-0371-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 06/25/2017] [Indexed: 01/28/2023]
Abstract
Alveolar macrophages are key contributors to both the promotion and resolution of inflammation in the lung and are categorized into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. The change in M1/M2 balance has been reported in various pulmonary diseases and is a target for therapeutic intervention. The aim of this study was to assess the modulation of M1/M2 phenotype in alveolar macrophages by water-soluble carbon monoxide-releasing molecule-3 (CORM-3). Rat alveolar macrophages (AM) (NR8383) in culture were stimulated with LPS (5 ng/ml)/IFN-γ (10 U/ml) or IL-4 (10 ng/ml)/IL-13 (10 ng/ml) to induce M1 and M2 phenotypes, respectively. Expression of M1 phenotype markers, iNOS and TNF-α, and M2 phenotype markers, CD206 and Ym-1, was assessed by western blotting after 1, 3, 6, or 24 h in the absence or presence of CORM-3 (0.15 mM) treatment. Inactive CORM-3 (iCORM-3) was used as a control. Treatment of naïve (unstimulated) AM with CORM-3 promoted progression of the M2 phenotype as evidenced by the increased expression of CD206 (at 1 h; 1.8-fold) and Ym-1 (at 3 h; 1.9-fold), respectively. Surprisingly, CORM-3 treatment also upregulated the expression of iNOS protein as assessed 6 h following stimulation of AM with CORM-3 (2.6-fold). On the contrary, CORM-3 effectively reduced LPS/IFN-γ-induced expression of iNOS protein (0.6-fold); however, it had no effect on TNF-α expression. Finally, CORM-3 acutely (1-3 h) upregulated CD206 (1.4-fold) and Ym-1 (1.6-fold) levels in IL-4-/IL-13-treated (M2-stimulus) macrophages. These findings indicate that CORM-3 modulates macrophage M1 and M2 phenotypes in vitro with respect to continuous suppression of iNOS expression in M1-polarized macrophages and transient (early-phase) upregulation of CD206 and Ym-1 proteins in M2-polarized macrophages.
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Affiliation(s)
- Hiroko Yamamoto-Oka
- Department of General Thoracic Surgery, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Shinjiro Mizuguchi
- Department of General Thoracic Surgery, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
| | - Michihito Toda
- Department of General Thoracic Surgery, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
| | - Yukiko Minamiyama
- Department of Food Science and Nutrition Health, Kyoto Prefectural University, Kyoto, Japan
| | - Shigekazu Takemura
- Department Hepato-Biliary-Pancreatic Surgery, Osaka City University, Osaka, Japan
| | - Toshihiko Shibata
- Department of General Thoracic Surgery, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.,Department of Food Science and Nutrition Health, Kyoto Prefectural University, Kyoto, Japan.,Department Hepato-Biliary-Pancreatic Surgery, Osaka City University, Osaka, Japan
| | - Gediminas Cepinskas
- Centre for Critical Illness Research, Lawson Health Research Institute, London, ON, Canada
| | - Noritoshi Nishiyama
- Department of General Thoracic Surgery, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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14
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Heftdal LD, Stengaard-Pedersen K, Ørnbjerg LM, Hetland ML, Hørslev-Petersen K, Junker P, Østergaard M, Hvid M, Deleuran B, Møller HJ, Greisen SR. Soluble CD206 plasma levels in rheumatoid arthritis reflect decrease in disease activity. Scandinavian Journal of Clinical and Laboratory Investigation 2017; 77:385-389. [PMID: 28598681 DOI: 10.1080/00365513.2017.1331462] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and infiltration by activated macrophages. TNFα is a central mediator in this process. The mannose receptor, CD206, is a scavenger receptor expressed by M2A-macrophages and dendritic cells. It is involved in collagen internalization and degradation. The soluble form has been suggested as a biomarker of M2A-macrophage activation. The aim of this study was to investigate sCD206 plasma levels in early RA patients initiating anti-TNFα treatment. Plasma levels of sCD206 were measured by ELISA in samples from 155 early RA patients with an average symptom duration of 3 months. Patients were randomized to 12 months' methotrexate and placebo (PLA) or methotrexate and adalimumab (ADA) treatment, followed by open-label treatment with disease-modifying anti-rheumatic drugs (DMARD) and if needed, ADA. Disease activity was assessed at baseline and after 3, 6, 12 and 24 months. Baseline plasma level of sCD206 in treatment naïve RA patients was 0.33 mg/L (CI: 0.33-0.38 mg/L) corresponding to the upper part of the reference interval for healthy controls (0.10-0.43 mg/L). In the PLA group, sCD206 levels decreased after 3 months, but did not differ from baseline after 6 months. In the ADA group, however, levels remained lower than baseline throughout the treatment period. In conclusion, initially, plasma sCD206 in early RA patients decreased in accordance with disease activity and initiation of DMARD treatment. Treatment with anti-TNFα preserved this decrease throughout the study period.
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Affiliation(s)
- Line Dam Heftdal
- a Department of Biomedicine , Aarhus University , Aarhus , Denmark
| | | | - Lykke Midtbøll Ørnbjerg
- c Center for Rheumatology and Spine Diseases , Copenhagen Center for Arthritis Research, Rigshospitalet , Glostrup , Denmark
| | - Merete Lund Hetland
- c Center for Rheumatology and Spine Diseases , Copenhagen Center for Arthritis Research, Rigshospitalet , Glostrup , Denmark.,d Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Kim Hørslev-Petersen
- e Department of Rheumatology , Kong Christian 10th Hospital for the Rheumatic Diseases , Graasten , Denmark.,f Institute of Health Research , University of Southern Denmark , Odense , Denmark
| | - Peter Junker
- g Department of Rheumatology , Odense University Hospital , Odense , Denmark
| | - Mikkel Østergaard
- c Center for Rheumatology and Spine Diseases , Copenhagen Center for Arthritis Research, Rigshospitalet , Glostrup , Denmark.,d Department of Clinical Medicine, Faculty of Health and Medical Sciences , University of Copenhagen , Copenhagen , Denmark
| | - Malene Hvid
- a Department of Biomedicine , Aarhus University , Aarhus , Denmark.,h Department of Clinical Medicine , Aarhus University , Aarhus , Denmark
| | - Bent Deleuran
- a Department of Biomedicine , Aarhus University , Aarhus , Denmark.,b Department of Rheumatology , Aarhus University Hospital , Aarhus , Denmark.,h Department of Clinical Medicine , Aarhus University , Aarhus , Denmark
| | - Holger Jon Møller
- i Department of Clinical Biochemistry , Aarhus University Hospital , Aarhus , Denmark
| | - Stinne Ravn Greisen
- a Department of Biomedicine , Aarhus University , Aarhus , Denmark.,b Department of Rheumatology , Aarhus University Hospital , Aarhus , Denmark
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15
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Laursen TL, Rødgaard-Hansen S, Møller HJ, Mortensen C, Karlsen S, Nielsen DT, Frevert S, Clemmesen JO, Møller S, Jensen JS, Bendtsen F, Grønbaek H. The soluble mannose receptor is released from the liver in cirrhotic patients, but is not associated with bacterial translocation. Liver Int 2017; 37:569-575. [PMID: 27706896 DOI: 10.1111/liv.13262] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Accepted: 09/23/2016] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Intestinal bacterial translocation is involved in activation of liver macrophages in cirrhotic patients. Macrophages play a key role in liver inflammation and are involved in the pathogenesis of cirrhosis and complications. Bacterial translocation may be determined by presence of bacterial DNA and macrophage activation, by the soluble mannose receptor. We hypothesize that the soluble mannose receptor is released from hepatic macrophages in cirrhosis and associated with bacterial DNA, portal pressure and complications. METHODS We investigated 28 cirrhotic patients set for transjugular intrahepatic portosystemic shunt insertion as a result of refractory ascites (n=17), acute (n=3), or recurrent variceal bleeding (n=8). We analysed plasma from the portal and hepatic veins for bacterial DNA and soluble mannose receptor with qPCR and ELISA. RESULTS The median soluble mannose receptor level was elevated in the hepatic vein compared with the portal vein (0.57(interquartile range 0.31) vs 0.55(0.40) mg/L, P=.005). The soluble mannose receptor levels were similar in bacterial DNA-positive and -negative patients. The soluble mannose receptor level in the portal and hepatic veins correlated with the portal pressure prior to transjugular intrahepatic portosystemic shunt insertion (r=.52, P<.008, both) and the levels correlated with Child-Pugh score (r=.63 and r=.56, P<.004, both). We observed higher soluble mannose receptor levels in patients with acute variceal bleeding compared to other indications (P<.05). CONCLUSION This study showed hepatic soluble mannose receptor excretion with a higher level in the hepatic than the portal vein, though with no associations to bacterial DNA. We observed associations between soluble mannose receptor levels and portal pressure and higher levels in patients with acute variceal bleeding indicating the soluble mannose receptor as a marker of complications of cirrhosis, but not bacterial translocation.
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Affiliation(s)
- Tea L Laursen
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger J Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Christian Mortensen
- Department of Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Stine Karlsen
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Dennis T Nielsen
- Department of Radiology, Aarhus University Hospital, Aarhus, Denmark
| | - Susanne Frevert
- Department of Radiology, Rigshospitalet, Copenhagen, Denmark
| | | | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional Imaging and Research, Hvidovre University Hospital, Hvidovre, Denmark
| | - Jørgen S Jensen
- Mycoplasma Laboratory, Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark
| | - Flemming Bendtsen
- Department of Gastroenterology, Hvidovre University Hospital, Hvidovre, Denmark
| | - Henning Grønbaek
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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16
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Tien WS, Chen JH, Wu KP. SheddomeDB: the ectodomain shedding database for membrane-bound shed markers. BMC Bioinformatics 2017; 18:42. [PMID: 28361715 PMCID: PMC5374707 DOI: 10.1186/s12859-017-1465-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND A number of membrane-anchored proteins are known to be released from cell surface via ectodomain shedding. The cleavage and release of membrane proteins has been shown to modulate various cellular processes and disease pathologies. Numerous studies revealed that cell membrane molecules of diverse functional groups are subjected to proteolytic cleavage, and the released soluble form of proteins may modulate various signaling processes. Therefore, in addition to the secreted protein markers that undergo secretion through the secretory pathway, the shed membrane proteins may comprise an additional resource of noninvasive and accessible biomarkers. In this context, identifying the membrane-bound proteins that will be shed has become important in the discovery of clinically noninvasive biomarkers. Nevertheless, a data repository for biological and clinical researchers to review the shedding information, which is experimentally validated, for membrane-bound protein shed markers is still lacking. RESULTS In this study, the database SheddomeDB was developed to integrate publicly available data of the shed membrane proteins. A comprehensive literature survey was performed to collect the membrane proteins that were verified to be cleaved or released in the supernatant by immunological-based validation experiments. From 436 studies on shedding, 401 validated shed membrane proteins were included, among which 199 shed membrane proteins have not been annotated or validated yet by existing cleavage databases. SheddomeDB attempted to provide a comprehensive shedding report, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. In addition, our published tool ShedP was embedded into SheddomeDB to support researchers for predicting the shedding event on unknown or unrecorded membrane proteins. CONCLUSIONS To the best of our knowledge, SheddomeDB is the first database for the identification of experimentally validated shed membrane proteins and currently may provide the most number of membrane proteins for reviewing the shedding information. The database included membrane-bound shed markers associated with numerous cellular processes and diseases, and some of these markers are potential novel markers because they are not annotated or validated yet in other databases. SheddomeDB may provide a useful resource for discovering membrane-bound shed markers. The interactive web of SheddomeDB is publicly available at http://bal.ym.edu.tw/SheddomeDB/ .
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Affiliation(s)
- Wei-Sheng Tien
- Institute of Biomedical Informatics, National Yang Ming University, Taipei, 112, Taiwan.,Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, 115, Taiwan
| | - Jun-Hong Chen
- Department of Computer Science, National Taipei University of Education, Taipei, 106, Taiwan
| | - Kun-Pin Wu
- Institute of Biomedical Informatics, National Yang Ming University, Taipei, 112, Taiwan.
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17
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Abstract
Receptor-targeted drug delivery has been extensively explored for active targeting. However, the scarce clinical applications of such delivery systems highlight the implicit hurdles in development of such systems. These hurdles begin with lack of knowledge of differential expression of receptors, their accessibility and identification of newer receptors. Similarly, ligand-specific challenges range from proper choice of ligand and conjugation chemistry, to release of drug/delivery system from ligand. Finally, nanocarrier systems, which offer improved loading, biocompatibility and reduced premature degradation, also face multiple challenges. This review focuses on understanding these challenges, and means to overcome such challenges to develop efficient, targeted drug-delivery systems.
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18
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Grønbæk H, Rødgaard-Hansen S, Aagaard NK, Arroyo V, Moestrup SK, Garcia E, Solà E, Domenicali M, Piano S, Vilstrup H, Møller HJ. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). J Hepatol 2016; 64:813-22. [PMID: 26639396 DOI: 10.1016/j.jhep.2015.11.021] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 10/21/2015] [Accepted: 11/17/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study. METHODS Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion. RESULTS We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)). CONCLUSIONS The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.
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Affiliation(s)
- Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | | | - Niels Kristian Aagaard
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Søren K Moestrup
- Department of Biomedicine, Aarhus University, Aarhus & Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | | | - Elsa Solà
- Liver Unit, Hospital Clinic de Barcelona, Unviersity of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Spain
| | - Marco Domenicali
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Salvatore Piano
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Hendrik Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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19
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Rødgaard-Hansen S, Rafique A, Christensen PA, Maniecki MB, Sandahl TD, Nexø E, Møller HJ. A soluble form of the macrophage-related mannose receptor (MR/CD206) is present in human serum and elevated in critical illness. Clin Chem Lab Med 2014; 52:453-61. [PMID: 24114918 DOI: 10.1515/cclm-2013-0451] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 09/04/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study tests the hypothesis that the mannose receptor (MR/CD206), which is expressed primarily by macrophages and dendritic cells, can be found in a soluble form (sMR, sMR) in human serum. Furthermore, we wished to establish and validate an enzyme-linked immunosorbent assay (ELISA) for sMR and to perform initial studies exploring the potential of sMR as a biomarker. METHODS Western blotting identified a single band of approximately 170 kDa in human serum, and MALDI MS/MS of the purified protein confirmed it to be sMR. An ELISA was established and validated with a measurement range of 1-256 µg/L. RESULTS The 95% reference interval was 0.10-0.43 mg/L based on measurements of serum samples from healthy individuals (n=217). Samples from hospitalised patients (n=219) revealed that more than 50% of patients had concentrations above 0.43 mg/L. Very high concentrations (up to 6.2 mg/L) were observed in critically ill patients with sepsis and/or severe liver disease. CONCLUSIONS This study documents, for the first time, the presence of sMR in human serum and describes an optimised ELISA suitable for quantitative measurements. Levels of sMR are strongly elevated in several disease states, including sepsis and liver disease, and the protein therefore shows promise as a new biomarker.
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20
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Mannose Receptor Ligands Regulate the Gene Expression of Toll-like Receptors in Chicken Monocytes. J Poult Sci 2013. [DOI: 10.2141/jpsa.0120178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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21
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Abstract
The MR is a highly effective endocytic receptor with a broad binding specificity encompassing ligands of microbial and endogenous origin and a poorly characterized ability to modulate cellular activation. This review provides an update of the latest developments in the field. It discusses how MR biology might be affected by glycosylation and proteolytic processing, MR involvement in antigen delivery, and the potential contribution of MR to T cell differentiation and cellular activation. Further understanding of these areas will, no doubt, inform the design of novel, therapeutic tools for improved vaccination, control of inflammation, and tumor chemotherapy, which will benefit from exploiting MR-efficient internalization properties and unique pattern of expression.
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Affiliation(s)
- Luisa Martinez-Pomares
- Faculty of Medicine and Health Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, United Kingdom.
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22
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Paul-Clark MJ, George PM, Gatheral T, Parzych K, Wright WR, Crawford D, Bailey LK, Reed DM, Mitchell JA. Pharmacology and therapeutic potential of pattern recognition receptors. Pharmacol Ther 2012; 135:200-15. [PMID: 22627269 DOI: 10.1016/j.pharmthera.2012.05.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 04/20/2012] [Indexed: 12/30/2022]
Abstract
Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.
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Affiliation(s)
- M J Paul-Clark
- Department of Cardiothoracic Pharmacology, Pharmacology and Toxicology, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse Street, London SW3 6LY, United Kingdom.
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23
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Gazi U, Rosas M, Singh S, Heinsbroek S, Haq I, Johnson S, Brown GD, Williams DL, Taylor PR, Martinez-Pomares L. Fungal recognition enhances mannose receptor shedding through dectin-1 engagement. J Biol Chem 2011; 286:7822-7829. [PMID: 21205820 PMCID: PMC3048669 DOI: 10.1074/jbc.m110.185025] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The mannose receptor (MR) is an endocytic type I membrane molecule with a broad ligand specificity that is involved in both hemostasis and pathogen recognition. Membrane-anchored MR is cleaved by a metalloproteinase into functional soluble MR (sMR) composed of the extracellular domains of intact MR. Although sMR production was initially considered a constitutive process, enhanced MR shedding has been observed in response to the fungal pathogen Pneumocystis carinii. In this work, we have investigated the mechanism mediating enhanced MR shedding in response to fungi. We show that other fungal species, including Candida albicans and Aspergillus fumigatus, together with zymosan, a preparation of the cell wall of Saccharomyces cerevisiae, mimic the effect of P. carinii on sMR production and that this effect takes place mainly through β-glucan recognition. Additionally, we demonstrate that MR cleavage in response to C. albicans and bioactive particulate β-glucan requires expression of dectin-1. Our data, obtained using specific inhibitors, are consistent with the canonical Syk-mediated pathway triggered by dectin-1 being mainly responsible for inducing MR shedding, with Raf-1 being partially involved. As in the case of steady-state conditions, MR shedding in response to C. albicans and β-glucan particles requires metalloprotease activity. The induction of MR shedding by dectin-1 has clear implications for the role of MR in fungal recognition, as sMR was previously shown to retain the ability to bind fungal pathogens and can interact with numerous host molecules, including lysosomal hydrolases. Thus, MR cleavage could also impact on the magnitude of inflammation during fungal infection.
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Affiliation(s)
- Umut Gazi
- From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Marcela Rosas
- the Department of Infection, Immunity, and Biochemistry, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
| | - Sonali Singh
- From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Sigrid Heinsbroek
- the Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Imran Haq
- Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,; Division of Therapeutics and Molecular Medicine, and
| | - Simon Johnson
- Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,; Division of Therapeutics and Molecular Medicine, and
| | - Gordon D Brown
- the Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 3FX, Scotland, United Kingdom, and
| | - David L Williams
- the Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614
| | - Philip R Taylor
- the Department of Infection, Immunity, and Biochemistry, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
| | - Luisa Martinez-Pomares
- From the School of Molecular Medical Sciences,; Respiratory Biomedical Research Unit, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,.
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Fievez V, Plapied L, des Rieux A, Pourcelle V, Freichels H, Wascotte V, Vanderhaeghen ML, Jerôme C, Vanderplasschen A, Marchand-Brynaert J, Schneider YJ, Préat V. Targeting nanoparticles to M cells with non-peptidic ligands for oral vaccination. Eur J Pharm Biopharm 2009; 73:16-24. [DOI: 10.1016/j.ejpb.2009.04.009] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 04/02/2009] [Accepted: 04/21/2009] [Indexed: 01/04/2023]
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25
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Martinez-Pomares L. The homeostatic properties of the mannose receptor in health and disease. ACTA ACUST UNITED AC 2008. [DOI: 10.1016/s0213-9626(08)70061-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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26
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Antigen capture of Porphyromonas gingivalis by human macrophages is enhanced but killing and antigen presentation are reduced by endotoxin tolerance. Infect Immun 2007; 76:477-85. [PMID: 17998310 DOI: 10.1128/iai.00100-07] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The innate and the adaptive arms of the mucosal immune system must be coordinated to facilitate the control of pathogenic invasion while maintaining immune homeostasis. Toll-like receptors, able to activate the cell to produce bactericidal and inflammatory cytokines but also able to upregulate antigen (Ag)-presenting and costimulatory molecules, are particularly important in this regard. We have previously shown that the chronically infected oral mucosa is in a state of endotoxin tolerance, as evidenced by the downregulation of Toll-like receptors 2 and 4 and of inflammatory cytokines and the upregulation of SH2-containing inositol phosphatase, an inhibitor of NF-kappaB signaling. In the present study, we hypothesized that endotoxin tolerance would influence the ability of human macrophages to engage in Ag capture and killing of the oral pathogen Porphyromonas gingivalis and to upregulate costimulatory molecules and stimulate autologous T-cell proliferation. We show that uptake, but not killing, of P. gingivalis 381 is enhanced by endotoxin tolerance. Reduced killing is possibly due to a reduction of the intracellular lysosomes. We further show that the expression of the Ag-presenting molecule HLA-DR and costimulatory molecules CD40 and CD86 is dampened by endotoxin tolerance to the constitutive level. This, along with our previous evidence for reduction in immunostimulatory cytokines, is consistent with the observed decrease in the induction of autologous CD4(+) T-cell proliferation by endotoxin-tolerized macrophages. Overall, these studies suggest that endotoxin tolerance, as observed in the inflamed oral mucosa, potentiates the innate Ag capture activity of macrophages but diminishes the potential of human macrophages to initiate the adaptive immune response. In conclusion, endotoxin tolerance, while helpful in bacterial clearance and in surmounting excessive inflammatory tissue damage, could potentially reduce the (protective) adaptive immune response during chronic infections such as periodontitis.
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27
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Fabriek BO, Møller HJ, Vloet RPM, van Winsen LM, Hanemaaijer R, Teunissen CE, Uitdehaag BMJ, van den Berg TK, Dijkstra CD. Proteolytic shedding of the macrophage scavenger receptor CD163 in multiple sclerosis. J Neuroimmunol 2007; 187:179-86. [PMID: 17537523 DOI: 10.1016/j.jneuroim.2007.04.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2006] [Revised: 04/19/2007] [Accepted: 04/24/2007] [Indexed: 01/27/2023]
Abstract
The scavenger receptor CD163 is selectively expressed on tissue macrophages and human monocytes. CD163 has been implicated to play a role in the clearance of hemoglobin and in the regulation of cytokine production by macrophages. Membrane CD163 can be cleaved by matrix metalloproteinases (MMP) resulting in soluble CD163 (sCD163). In the present report the shedding of CD163 was investigated in multiple sclerosis (MS). An upregulation of plasma sCD163 and a down regulation of membrane CD163 in MS patients compared to healthy controls was observed. The levels of plasma sCD163 correlated with plasma MMP-9 levels in controls, but not in MS patients. Moreover, evidence was obtained for CD163-cleaving MMP activity in plasma of MS patients. Finally, the increased proteolytic shedding of CD163 correlated to reduced plasma levels of circulating inflammatory cytokines. Collectively, our results provide evidence for proteolytic shedding of CD163 in MS and suggest a possible link to cytokine production.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Animals
- Antigens, CD/blood
- Antigens, CD/immunology
- Antigens, Differentiation, Myelomonocytic/blood
- Antigens, Differentiation, Myelomonocytic/immunology
- Cell Line, Transformed
- Cricetinae
- Cricetulus
- Cytokines/metabolism
- Enzyme Inhibitors/pharmacology
- Enzyme-Linked Immunosorbent Assay/methods
- Female
- Humans
- Hydrocortisone/metabolism
- Male
- Matrix Metalloproteinase 2/metabolism
- Matrix Metalloproteinase 9/metabolism
- Middle Aged
- Multiple Sclerosis/blood
- Multiple Sclerosis/metabolism
- Receptors, Cell Surface/blood
- Receptors, Cell Surface/immunology
- Statistics, Nonparametric
- Transfection/methods
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Affiliation(s)
- Babs O Fabriek
- Department of Molecular Cell Biology and Immunology, VU Medical Center, The Netherlands
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28
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Mumper RJ, Cui Z, Oyewumi MO. Nanotemplate Engineering of Cell Specific Nanoparticles. J DISPER SCI TECHNOL 2007. [DOI: 10.1081/dis-120021814] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Russell J. Mumper
- a Division of Pharmaceutical Sciences , College of Pharmacy, University of Kentucky , Lexington , Kentucky , 40536‐0082 , USA
| | - Zhengrong Cui
- a Division of Pharmaceutical Sciences , College of Pharmacy, University of Kentucky , Lexington , Kentucky , 40536‐0082 , USA
| | - Moses O. Oyewumi
- a Division of Pharmaceutical Sciences , College of Pharmacy, University of Kentucky , Lexington , Kentucky , 40536‐0082 , USA
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29
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Mansour MK, Latz E, Levitz SM. Cryptococcus neoformans glycoantigens are captured by multiple lectin receptors and presented by dendritic cells. THE JOURNAL OF IMMUNOLOGY 2006; 176:3053-61. [PMID: 16493064 DOI: 10.4049/jimmunol.176.5.3053] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Cell-mediated immune responses to glycoantigens have been largely uncharacterized. Protective T cell responses to the pathogenic yeast Cryptococcus neoformans are dependent on heavily mannosylated Ags termed mannoproteins. In the work presented, the innate immune response to mannoprotein was determined. Purified murine splenic dendritic cells (DC), B cells, and macrophages were used to stimulate mannoprotein-specific T cells. Only DC were capable of any measurable stimulation. Depletion of DC resulted in the abrogation of the T cell response. Human and murine DC rapidly captured fluorescent-labeled mannoprotein by a mannose receptor-mediated process. Using transfected cell lines, the type II C-type lectin receptor DC-specific ICAM-3-grabbing nonintegrin (CD209) was determined to have affinity for mannoprotein. Taken together with prior work demonstrating that mannoprotein was captured by the macrophage mannose receptor (CD206), these data suggest that multiple mannose receptors on DC recognize mannoprotein. Pulsing experiments demonstrated that DC captured sufficient mannoprotein over 2 h to account for 50% of total stimulation. Capture appeared dependent on mannose receptors, as competitive mannosylated inhibitors and calcium chelators each interfered with T cell stimulation. By confocal microscopy, intracellular mannoprotein trafficked to an endo-lysosomal compartment in DC, and at later time points extended into tubules in a similar fashion to the degradation marker DQ-OVA. Mannoprotein colocalized intracellularly with CD206 and CD209. These data suggest that DC provide the crucial link between innate and adaptive immune responses to C. neoformans via a process that is dependent upon the efficient uptake of mannoprotein by mannose receptors.
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Affiliation(s)
- Michael K Mansour
- Department of Microbiology and Immunology Training Program, Boston University School of Medicine, Boston, MA 02118, USA
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30
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Li L, Xie X, Yang F. Identification and characterization of a prawn white spot syndrome virus gene that encodes an envelope protein VP31. Virology 2005; 340:125-32. [PMID: 16023692 DOI: 10.1016/j.virol.2005.06.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Revised: 05/09/2005] [Accepted: 06/03/2005] [Indexed: 11/20/2022]
Abstract
Based on a combination of SDS-PAGE and mass spectrometry, a protein with an apparent molecular mass of 31 kDa (termed as VP31) was identified from purified shrimp white spot syndrome virus (WSSV) envelope fraction. The resulting amino acid (aa) sequence matched an open reading frame (WSV340) of the WSSV genome. This ORF contained 783 nucleotides (nt), encoding 261 aa. A fragment of WSV340 was expressed in Escherichia coli as a glutathione S-transferase (GST) fusion protein with a 6His-tag, and then specific antibody was raised. Western blot analysis and the immunoelectron microscope method (IEM) confirmed that VP31 was present exclusively in the viral envelope fraction. The neutralization experiment suggested that VP31 might play an important role in WSSV infectivity.
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Affiliation(s)
- Li Li
- Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, Xiamen, P.R. China
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31
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Martinez-Pomares L, Hanitsch LG, Stillion R, Keshav S, Gordon S. Expression of mannose receptor and ligands for its cysteine-rich domain in venous sinuses of human spleen. J Transl Med 2005; 85:1238-49. [PMID: 16056240 DOI: 10.1038/labinvest.3700327] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
The mannose receptor (MR) is a type I membrane molecule with two lectin activities. Mannose recognition takes place through the C-type lectin-like carbohydrate recognition domains, while recognition of sulphated glycans is mediated by the cysteine-rich domain (CR). In murine spleen CR ligands are present in a subpopulation of macrophages (Mphi) placed in the marginal zone whereas MR-expressing cells consisting of Mphi and nonvascular endothelia are located in the red pulp. No colocalisation of MR with CR ligands has been observed in murine tissues. In this manuscript we describe the distribution of MR and CR ligands in human spleen. In this organ we have detected a perfect colocalisation of MR with CR ligands in Lyve-1+ cells lining venous sinuses. These cells form a physical barrier for blood cells as they need to migrate through the sinuses in order to exit the splenic parenchyma and, in this way, contribute to the unique filtration function of this organ. Furthermore, unlike murine spleen, CD68+ red pulp Mphi lack MR expression. Our results suggest an unexpected contribution of MR to splenic function through the recognition of sulphated ligands that could influence the filtering capability of this organ.
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MESH Headings
- Animals
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/metabolism
- Cysteine/genetics
- Galactosamine/chemistry
- Galactose/chemistry
- Gene Expression
- Glycoproteins/metabolism
- Humans
- Lectins, C-Type/chemistry
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Ligands
- Macrophages/metabolism
- Mannose Receptor
- Mannose-Binding Lectins/chemistry
- Mannose-Binding Lectins/genetics
- Mannose-Binding Lectins/metabolism
- Mice
- Protein Structure, Tertiary
- Rats
- Receptors, Cell Surface/chemistry
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Spleen/blood supply
- Spleen/metabolism
- Veins/metabolism
- Vesicular Transport Proteins
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32
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Su Y, Bakker T, Harris J, Tsang C, Brown GD, Wormald MR, Gordon S, Dwek RA, Rudd PM, Martinez-Pomares L. Glycosylation influences the lectin activities of the macrophage mannose receptor. J Biol Chem 2005; 280:32811-20. [PMID: 15983039 DOI: 10.1074/jbc.m503457200] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The mannose receptor (MR) is a heavily glycosylated endocytic receptor that recognizes both mannosylated and sulfated ligands through its C-type lectin domains and cysteine-rich (CR) domain, respectively. Differential binding properties have been described for MR isolated from different sources, and we hypothesized that this could be due to altered glycosylation. Using MR transductants and purified MR, we demonstrate that glycosylation differentially affects both MR lectin activities. MR transductants generated in glycosylation mutant cell lines lacked most mannose internalization activity, but could internalize sulfated glycans. Accordingly, purified MR bearing truncated Man5-GlcNAc2 glycans (Man5 -MR) or non-sialylated complex glycans (SA0-MR) did not bind mannosylated glycans, but could recognize SO4-3-Gal in vitro. Additional studies showed that, although mannose recognition was largely independent of the oligomerization state of the protein, recognition of sulfated carbohydrates was mostly mediated by self-associated MR and that, in SA0-MR, there was a higher proportion of oligomeric MR. These results suggest that self-association could lead to multiple presentation of CR domains and enhanced avidity for sulfated sugars and that non-sialylated MR is predisposed to oligomerize. Therefore, the glycosylation of MR, terminal sialylation in particular, could influence its binding properties at two levels. (i) It is required for mannose recognition; and (ii) it modulates the tendency of MR to self-associate, effectively regulating the avidity of the CR domain for sulfated sugar ligands.
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Affiliation(s)
- Yunpeng Su
- Glycobiology Institute and the Biochemistry Department, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom
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33
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Parrott MB, Adams KE, Mercier GT, Mok H, Campos SK, Barry MA. Metabolically biotinylated adenovirus for cell targeting, ligand screening, and vector purification. Mol Ther 2003; 8:688-700. [PMID: 14529842 DOI: 10.1016/s1525-0016(03)00213-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Development of cell-targeting vectors is an important focus for gene therapy. While some ligands can be genetically inserted into virus capsid proteins for cell targeting, for many ligands, this approach can disrupt either ligand function or vector function. To address this problem for adenovirus type 5 vectors, the fiber capsid protein was genetically fused to a biotin acceptor peptide (BAP). Adenovirus particles bearing this BAP were metabolically biotinylated during vector production by the endogenous biotin ligase in 293 cells to produce covalently biotinylated virions. The resulting biotinylated vector could be retargeted to new receptors by conjugation to biotinylated antibodies using tetrameric avidin (K(d) = 10(-15) M). The biotinylated vector could also be purified by biotin-reversible binding on monomeric avidin (K(d) = 10(-7) M). Finally, this vector was used as a ligand screening platform for dendritic cells in which a variety of structurally diverse protein, carbohydrate, and nucleic acid ligands were easily added to the vector using the biotin-avidin interaction. This work demonstrates the utility of metabolically biotinylated viruses for ligand screening, vector targeting, and virus purification applications.
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Affiliation(s)
- M Brandon Parrott
- Center for Cell and Gene Therapy and Department of Immunology, Rice University, Houston, Texas, USA
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34
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Cui Z, Hsu CH, Mumper RJ. Physical characterization and macrophage cell uptake of mannan-coated nanoparticles. Drug Dev Ind Pharm 2003; 29:689-700. [PMID: 12889787 DOI: 10.1081/ddc-120021318] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Previously, we reported on a cationic nanoparticle-based DNA vaccine delivery system engineered from warm oil-in-water microemulsion precursors. In these present studies, the feasibility of lyophilizing the nanoparticles and their thermal properties were investigated. Also, the binding and uptake of the nanoparticles by a macrophage cell line were studied. The nanoparticles (prior to pDNA coating) were freeze-dried with lactose or sucrose as cryoprotectants. The stability of lyophilized nanoparticles at room temperature was monitored and compared to that of the aqueous nanoparticle suspension. The thermal properties of the nanoparticles were investigated using differential scanning calorimetry (DSC). The nanoparticles, coated or uncoated with mannan as a ligand, were incubated with a mannose receptor positive (MR+) mouse macrophage cell line (J774E), at either 4 degrees C or 37 degrees C to study the binding and uptake of the nanoparticles by the cells. It was found that lactose or sucrose (1-5%, w/v) was required for successful lyophilization of the nanoparticles. After 4 months of storage, the size of lyophilized nanoparticles did not significantly increase while those in aqueous suspension grew by over 900%. Unlike its individual components, emulsifying wax (m.p., approximately 55 degrees C) and hexadecyltrimethyl ammonium bromide, the nanoparticles showed a melting point of approximately 90 degrees C. Moreover, the DSC profile of the nanoparticles was different from that of the physical mixture of emulsifying wax and CTAB. After 1 hour incubation at 37 degrees C, the uptake of mannan-coated nanoparticles was 50% higher than that of the uncoated nanoparticles. At 4 degrees C and after one hour, the binding of the mannan-coated nanoparticles by J774E was over 2-fold higher than that of the uncoated nanoparticles. This increase in J774E binding could be abolished by preincubating the cells with free mannan, suggesting that the binding and uptake were receptor-mediated. In conclusion, the nanoparticles were lyophilizable, and lyophilization was shown to enhance the stability of the nanoparticles. DSC provided evidence that the nanoparticles were not a physical mixture of their individual components. Finally, cell binding and uptake studies demonstrated that the nanoparticles have potential application for cell-specific targeting.
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Affiliation(s)
- Zhengrong Cui
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA
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35
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Abstract
Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1-phosphate). Other sphingolipid metabolites such as ceramide 1-phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage-targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar N-butyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.
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Affiliation(s)
- Timothy M Cox
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
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36
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Martinez-Pomares L, Reid DM, Brown GD, Taylor PR, Stillion RJ, Linehan SA, Zamze S, Gordon S, Wong SYC. Analysis of mannose receptor regulation by IL-4, IL-10, and proteolytic processing using novel monoclonal antibodies. J Leukoc Biol 2003; 73:604-13. [PMID: 12714575 DOI: 10.1189/jlb.0902450] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The study of the murine macrophage mannose receptor (MR) has been hampered by the lack of specific reagents. We have generated and characterized novel anti-MR monoclonal antibodies and used them to analyze MR expression in primary mouse macrophages (M(phi)). In BioGel- and thioglycollate-elicited M(phi), interleukin (IL)-4 up-regulated total cell-associated MR (cMR), correlating with enhanced surface expression. We investigated the influence of IL-10, a well-characterized deactivator of M(phi) function, on MR levels and observed that it had a similar effect to IL-4. In both cases, enhanced cMR levels translated into increased production of the soluble form of the receptor (sMR). We have demonstrated the presence of sMR in cultures of stable non-M(phi) transductants expressing full-length MR, indicating that the proteolytic activity responsible for cMR cleavage is not M(phi)-restricted. These data support a role for the MR in T helper cell type 2 cytokine-driven, immune responses and suggest a non-M(phi) contribution to sMR production in vivo.
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MESH Headings
- 3T3 Cells
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Blotting, Western
- CHO Cells
- Cell Line
- Cricetinae
- Cricetulus
- Endocytosis
- Flow Cytometry
- Interleukin-10/pharmacology
- Interleukin-4/pharmacology
- Lectins, C-Type/biosynthesis
- Lectins, C-Type/genetics
- Lectins, C-Type/immunology
- Macrophages, Peritoneal/drug effects
- Macrophages, Peritoneal/metabolism
- Mannose/metabolism
- Mannose Receptor
- Mannose-Binding Lectins
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Receptors, Cell Surface/biosynthesis
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/immunology
- Recombinant Fusion Proteins
- Serum Albumin/metabolism
- Solubility
- Specific Pathogen-Free Organisms
- Th2 Cells/immunology
- Transduction, Genetic
- Up-Regulation/drug effects
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37
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Knight SC, Burke F, Bedford PA. Dendritic cells, antigen distribution and the initiation of primary immune responses to self and non-self antigens. Semin Cancer Biol 2002; 12:301-8. [PMID: 12147204 DOI: 10.1016/s1044-579x(02)00016-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Immunity or tolerance are determined through the bone marrow-derived, antigen-presenting cells, dendritic cells (DC). Stimulation of lymphocytes by different types of DC, DC at different stages of maturity and DC producing and responding to different growth factors modulate immune responses. Innate receptors for foreign or self antigens provide scope in DC for discrimination between different antigenic stimuli. DC also transfer processed antigens to other DC. We propose that DC do not stimulate responses to antigens in their own environment but only to antigens acquired from other DC, providing a mechanism for discriminating between environmental and non-environmental antigens.
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Affiliation(s)
- Stella C Knight
- Antigen Presentation Research Group, Northwick Park Institute for Medical Research, Imperial College Faculty of Medicine, Watford Rd., Harrow HA1 3UJ, UK.
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38
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Cui Z, Mumper RJ. Genetic immunization using nanoparticles engineered from microemulsion precursors. Pharm Res 2002; 19:939-46. [PMID: 12180545 DOI: 10.1023/a:1016402019380] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Genetic immunization using "naked" plasmid DNA (pDNA) has been shown to elicit broad humoral and cellular immune responses. However, more versatile and perhaps cell-targeted delivery systems are needed. To this end, a novel process to engineer cationic nanoparticles coated with pDNA for genetic immunization was explored. METHODS; Cationic nanoparticles were engineered from warm oil-in-water microemulsion precursors composed of emulsifying wax as the oil phase and cetyltrimethylammonium bromide (CTAB) as the cationic surfactant. Plasmid DNA was coated on the surface of the cationic nanoparticles to produce pDNA-coated nanoparticles. An endosomolytic lipid and/or a dendritic cell-targeting ligand (mannan) were incorporated in or deposited on the nanoparticles to enhance the in vitro cell transfection efficiency and the in vivo immune responses after subcutaneous injection to Balb/C mice. The IgG titer to expressed beta-galactosidase and the cytokine release from isolated splenocytes after stimulation were determined on 28 days. RESULTS Cationic nanoparticles (around 100 nm) were engineered within minutes. The pDNA-coated nanoparticles were stable at 37 degrees C over 30 min in selected biologic fluids. Transmission electron microscopy showed the nanoparticles were spherical. Plasmid DNA-coated nanoparticles. especially those with both an endosomolytic lipid and dendritic cell-targeting ligand. resulted in significant enhancement in both IgG titer (over 16-fold) and T-helper type-1 (Th1-type) cytokine release (up to 300% increase) over "naked" pDNA. CONCLUSION A novel method to engineer pDNA-coated nanoparticles for enhanced in vitro cell transfection and enhanced in vivo immune responses was reported.
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Affiliation(s)
- Zhengrong Cui
- Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington 40536-0082, USA
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Westbroek I, De Rooij KE, Nijweide PJ. Osteocyte-specific monoclonal antibody MAb OB7.3 is directed against Phex protein. J Bone Miner Res 2002; 17:845-53. [PMID: 12009015 DOI: 10.1359/jbmr.2002.17.5.845] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Osteocytes are the most abundant cells in bone; however, relatively little is known about their properties and functions. The development of monoclonal antibody MAb OB7.3 directed against chicken osteocytes enabled us to purify osteocytes from enzymatically isolated bone cells. Cultures of purified osteocytes were used to gain better insight into the role of osteocytes in bone metabolism. Until now, the antigen of MAb OB7.3 has not been elucidated. In this study, we examined the antigen to which this osteocyte-specific antibody is directed. Immunoprecipitation and purification of the protein, followed by amino acid sequence analysis of two isolated peptides, revealed that the antigen has high homology to human and murine PHEX/Phex protein sequences (PHosphate-regulating gene with homology to Endopeptidases on the X chromosome). The OB7.3 antigen was therefore identified as chicken Phex protein. In addition, using suppression subtractive hybridization, we obtained a complementary DNA (cDNA) sequence of 502 base pairs (bp) with high homology to the human and murine PHEX/Phex genes. This method was applied to identify genes, which are differentially expressed in osteocytes compared with osteoblasts. The results also suggest that Phex is expressed at higher levels in chicken osteocytes compared with osteoblasts. Reverse-transcription polymerase chain reaction (RT-PCR) and Northern blot analyses supported these findings. The function of Phex is not completely understood. However, it is known that the gene is preferentially expressed in bone and that mutations in PHEX/Phex lead to X-linked hypophosphatemia and bone mineralization abnormalities. Our findings suggest that osteocytes play an important role in the Phex-regulated phosphate handling in the kidney and in bone.
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Affiliation(s)
- Irene Westbroek
- Department of Molecular Cell Biology, Leiden University Medical Center, The Netherlands
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Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol 2002; 2:77-84. [PMID: 11910898 DOI: 10.1038/nri723] [Citation(s) in RCA: 605] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dendritic cells and Langerhans cells are specialized for the recognition of pathogens and have a pivotal role in the control of immunity. As guardians of the immune system, they are present in essentially every organ and tissue, where they operate at the interface of innate and acquired immunity. Recently, several C-type lectin and lectin-like receptors have been characterized that are expressed abundantly on the surface of these professional antigen-presenting cells. It is now becoming clear that lectin receptors not only serve as antigen receptors but also regulate the migration of dendritic cells and their interaction with lymphocytes.
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Affiliation(s)
- Carl G Figdor
- Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, NCMLS/187 Til, Postbox 9101, 6500HB Nijmegen, The Netherlands.
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Dello Sbarba P, Rovida E. Transmodulation of cell surface regulatory molecules via ectodomain shedding. Biol Chem 2002; 383:69-83. [PMID: 11928824 DOI: 10.1515/bc.2002.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cell responses to exogenous stimuli often result in a rapid decrease of cell surface density of a wide range of diverse regulatory proteins, receptor and adhesion molecules in particular. This decrease may occur in a ligand-dependent fashion (down-regulation), following endocytosis and degradation by lysosomal proteases, or by down-modulation, where molecules are targeted by endoproteases directly on cell surface. These proteases are recruited by trans-modulating agents, different from ligand, which act via their own receptors and the related intracellularly-generated signals. Endoproteolytic activity determines the release of large portions (shedding) of substrate proteins, called ectodomains, which are usually not ligand-bound, and therefore represent biologically-active molecules. Ectodomain shedding is involved in a number of pathophysiological processes, such as inflammation, cell degeneration and apoptosis, and oncogenesis. Common features of the process, such as the involvement of protein kinase C and of transmembrane metalloproteases, have been identified. In this review, we summarize basic concepts on down-modulation and ectodomain shedding, and provide an update of the issue with respect to: (i) new entries to the list of molecules found involved in the process; (ii) current views about the upstream control of shedding, i.e. the pathways linking the signals triggered by the trans-modulating agents to the activation of endoproteolytic activity on the cell surface.
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Affiliation(s)
- Persio Dello Sbarba
- Dipartimento di Patologia e Oncologia Sperimentali, Università di Firenze, Italy
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Croizet K, Trouttet-Masson S, Rabilloud R, Nicolas JF, Bernier-Valentin F, Rousset B. Signaling from epithelial to dendritic cells of the thyroid gland: evidence for thyrocyte-derived factors controlling the survival, multiplication, and endocytic activity of dendritic cells. J Transl Med 2001; 81:1601-13. [PMID: 11742031 DOI: 10.1038/labinvest.3780374] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Intrathyroidal dendritic cells (DC) isolated at the same time and then cultured with thyrocytes in the presence of thyrotropin (TSH) keep a phenotype of immature DC (Croizet et al, 2000). As DC from other sources are known to undergo a rapid maturation in vitro, we hypothesized that the maintenance of thyroid-derived DC in an immature state might be caused by thyrocytes-DC interactions. In this study, we investigated whether thyroid-derived DC could change their phenotype in response to TSH stimulation of thyrocytes. Over an 8-day period of culture, the population of DC increased 2- to 3-fold in the presence of TSH and decreased by more than 75% in the absence of TSH. The increase in the DC population was related to DC proliferation, whereas the reduction of the number of DC was secondary to a loss of cell-substrate adhesion and subsequent cell death. In the presence of TSH, DC acquired and maintained a high capacity for internalizing labeled ligands, expressed the mannose receptor, and exposed MHC class II molecules at the cell surface. On the contrary, DC cultured without TSH were devoid of endocytic activity and mannose receptor and, after 2 days, no longer exposed MHC class II molecules at the cell surface. Using conditioned media and enriched DC populations, we show that thyrocytes, in response to TSH, produce soluble factors capable of activating proliferation and endocytic activity of DC. Exogenous granulocyte/macrophage-colony stimulating factor and transforming growth factor-beta, known to be produced by thyrocytes, reproduced the effects of conditioned media. These data, giving evidence of a hormone-regulated signaling process between epithelial and dendritic cells in vitro, suggest that thyrocytes could promote the maintenance of a population of immature DC within the thyroid gland.
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Affiliation(s)
- K Croizet
- INSERM U-369, Faculté de Médecine Lyon-RTH Laennec, Lyon, France
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Stehle SE, Rogers RA, Harmsen AG, Ezekowitz RA. A soluble mannose receptor immunoadhesin enhances phagocytosis of Pneumocystis carinii by human polymorphonuclear leukocytes in vitro. Scand J Immunol 2000; 52:131-7. [PMID: 10931380 DOI: 10.1046/j.1365-3083.2000.00755.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Pneumocystis carinii is an opportunistic pathogen that causes pneumonia in immunocompromised hosts. In the normal host, P. carinii is susceptible to an array of first line host defense mechanisms that are operative in the lung. Alveolar macrophages play a central role in the clearance of inhaled organisms. The macrophage mannose receptor (MR) appears to be sufficient for P. carinii phagocytosis. In individuals infected with the human immunodeficiency virus, MR expression on alveolar macrophages and P. carinii phagocytosis are decreased, however, Fc-receptor mediated phagocytosis remains intact. In this study, we demonstrate that a recombinant soluble MR immunoadhesin, consisting of the essential carbohydrate binding MR ectodomain and the Fc-region of human immunoglobulin (Ig)G1, binds P. carinii and leads to an 8.2-fold increased uptake of P. carinii by phagocytic cells. Our results suggest that the soluble MR immunoadhesin may have therapeutic potential in the treatment of P. carinii infections.
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Affiliation(s)
- S E Stehle
- Laboratory of Developmental Immunology, MassGeneral Hospital for Children, and Harvard Medical School, Boston, Massachusetts 02114, USA
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Parrott MB, Barry MA. Metabolic biotinylation of recombinant proteins in mammalian cells and in mice. Mol Ther 2000; 1:96-104. [PMID: 10933917 PMCID: PMC2002494 DOI: 10.1006/mthe.1999.0011] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The avidin-biotin system is a fundamental technology in biomedicine for immunolocalization, imaging, nucleic acid blotting, and protein labeling. While this technology is robust, it is limited by the fact that mammalian proteins must be expressed and purified prior to chemical biotinylation using cross-linking agents which modify proteins at random locations to heterogeneous levels and can inactivate protein function. To circumvent this limitation, we demonstrate the ability to metabolically biotinylate tagged proteins in mammalian cells and in mice using the endogenous biotinylation enzymes of the host. Endogenously biotinylated proteins were readily purified from mammalian cells using monomeric avidin and eluted under nondenaturing conditions using only biotin as the releasing agent. This technology should allow recombinant proteins and fragile protein complexes to be produced and purified from mammalian cells as well as from transgenic plants and animals. In addition, this technology may be particularly useful for cell-targeting applications in which proteins or viral gene therapy vectors can be biotinylated at genetically defined sites for combination with other targeting moieties complexed with avidin.
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Affiliation(s)
- M B Parrott
- Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
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