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1
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Wu M, Sapin-Minet A, Gaucher C. Heparin, an active excipient to carry biosignal molecules: Applications in tissue engineering - A review. Int J Biol Macromol 2025; 312:143959. [PMID: 40334894 DOI: 10.1016/j.ijbiomac.2025.143959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 04/29/2025] [Accepted: 05/04/2025] [Indexed: 05/09/2025]
Abstract
Drug repositioning refers to new medical application exploration for existing drugs. Heparins, beyond their well-known anticoagulant properties widely used in clinics, present the capacity to carry biosignal molecules that is responsible for other properties such as anti-inflammatory, angiogenesis. Thus, heparins interaction with different biosignal molecules such as cytokines and growth factors have recently drawn attention and have promoted heparin repositioning as an active excipient with useful applications as drug-delivery systems and biomaterial-based tissue engineering scaffolds. Indeed, biomaterial heparinization can further help in their formulation such as in self-assembled heparin-based hydrogels or nanoparticles, and improve their biocompatibility. Moreover, the capacity of heparin to carry biosignal molecules enables the direct functionalization of heparinized biomaterial for tissue engineering. Both heparin characteristics namely the biosignal molecule carrying and biomaterial heparinization are reviewed here along their combination for biomaterial functionalization in tissue engineering applications.
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Affiliation(s)
- Meiling Wu
- Université de Lorraine, CITHEFOR, F-54000 Nancy, France
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2
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Parween F, Singh SP, Kathuria N, Zhang HH, Ashida S, Otaizo-Carrasquero FA, Shamsaddini A, Gardina PJ, Ganesan S, Kabat J, Lorenzi HA, Riley DJ, Myers TG, Pittaluga S, Bielekova B, Farber JM. Migration arrest and transendothelial trafficking of human pathogenic-like Th17 cells are mediated by differentially positioned chemokines. Nat Commun 2025; 16:1978. [PMID: 40000641 PMCID: PMC11861662 DOI: 10.1038/s41467-025-57002-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Human Th17/type 17 cells express the chemokine receptor CCR6, but the functions of CCR6 and other chemokine receptors in human type 17 Th cell extravasation have not been fully delineated. Here we show that human peripheral blood CD4+CCR6+ T cells co-expressing CCR2 have a pathogenic Th17 signature, can produce inflammatory cytokines without T cell receptor activation, and show enhanced expression of pathogenicity-associated and activation-associated genes in the cerebrospinal fluid of patients with multiple sclerosis as compared to controls. In flow chambers with activated endothelial cell (EC) monolayers, CD4+CCR6+CCR2+ T cells are efficient at transendothelial migration (TEM). Ligands for CCR5, CCR6 and CXCR3 localize to EC surfaces and mediate only arrest, whereas CCR2 ligands fail to bind well to ECs and mediate only TEM. Conversely, expressing a chimeric CCR2 ligand engineered to bind glycosaminoglycans on ECs results in CCR2-mediated arrest but blocks TEM induction. Our results from human pathogenic-like type 17 cells thus suggest that T cell migration arrest requires chemokine bound to EC surfaces, whereas TEM requires a transendothelial chemokine gradient.
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Affiliation(s)
- Farhat Parween
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Satya P Singh
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Nausheen Kathuria
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hongwei H Zhang
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shinji Ashida
- Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Francisco A Otaizo-Carrasquero
- Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Amirhossein Shamsaddini
- Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Paul J Gardina
- Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sundar Ganesan
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Juraj Kabat
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hernan A Lorenzi
- Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Deanna J Riley
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Timothy G Myers
- Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bibiana Bielekova
- Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Joshua M Farber
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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3
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Wu X, Zhao X, Li F, Wang Y, Ou Y, Zhang H, Li X, Wu X, Wang L, Li M, Zhang Y, Liu J, Xing M, Liu H, Tan Y, Wang Y, Xie Y, Zhang H, Luo Y, Li H, Wang J, Sun L, Li Y, Zhang H. MLKL-mediated endothelial necroptosis drives vascular damage and mortality in systemic inflammatory response syndrome. Cell Mol Immunol 2024; 21:1309-1321. [PMID: 39349742 PMCID: PMC11527879 DOI: 10.1038/s41423-024-01217-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 09/11/2024] [Indexed: 11/02/2024] Open
Abstract
The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction syndrome (MODS) and mortality. Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS, the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear. In this study, we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin (NAH) pretreatment protect mice against TNF-α-induced mortality in SIRS. Moreover, the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS. These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality. Furthermore, using a genetic lineage tracing mouse model (Tie2-Cre;Rosa26-tdT), we tracked endothelial cells (ECs) and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice. Importantly, Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium. Collectively, our findings demonstrated that RIPK3-MLKL-dependent necroptosis disrupted vascular integrity, resulting in coagulopathy and multiorgan failure, eventually leading to mortality in SIRS patients. These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
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Affiliation(s)
- Xiaoxia Wu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xiaoming Zhao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Fang Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yang Wang
- Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yangjing Ou
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Haiwei Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xiaoming Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xuanhui Wu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Lingxia Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Ming Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Yue Zhang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jianling Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Mingyan Xing
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Han Liu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Yongchang Tan
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yangyang Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Yangyang Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Hanwen Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Yan Luo
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hong Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Jing Wang
- Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Liming Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, PR China
| | - Yu Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, PR China.
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4
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Lee NY, Ture HY, Lee EJ, Jang JA, Kim G, Nam EJ. Syndecan-1 Plays a Role in the Pathogenesis of Sjögren's Disease by Inducing B-Cell Chemotaxis through CXCL13-Heparan Sulfate Interaction. Int J Mol Sci 2024; 25:9375. [PMID: 39273320 PMCID: PMC11394922 DOI: 10.3390/ijms25179375] [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: 07/30/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
In Sjögren's disease (SjD), the salivary glandular epithelial cells can induce the chemotaxis of B cells by secreting B-cell chemokines such as C-X-C motif chemokine ligand 13 (CXCL13). Syndecan-1 (SDC-1) is a major transmembrane heparan sulfate proteoglycan (HSPG) predominantly expressed on epithelial cells that binds to and regulates heparan sulfate (HS)-binding molecules, including chemokines. We aimed to determine whether SDC-1 plays a role in the pathogenesis of SjD by acting on the binding of HS to B-cell chemokines. To assess changes in glandular inflammation and SDC-1 concentrations in the submandibular gland (SMG) and blood, female NOD/ShiLtJ and sex- and age-matched C57BL/10 mice were used. In the SMG of NOD/ShiLtJ mice, inflammatory responses were identified at 8 weeks of age, but increased SDC-1 concentrations in the SMG and blood were observed at 6 weeks of age, when inflammation had not yet started. As the inflammation of the SMG worsened, the SDC-1 concentrations in the SMG and blood increased. The expression of the CXCL13 and its receptor C-X-C chemokine receptor type 5 (CXCR5) began to increase in the SMG at 6 weeks of age and continued until 12 weeks of age. Immunofluorescence staining in SMG tissue and normal murine mammary gland cells confirmed the co-localization of SDC-1 and CXCL13, and SDC-1 formed a complex with CXCL13 in an immunoprecipitation assay. Furthermore, NOD/ShiLtJ mice were treated with 5 mg/kg HS intraperitoneally thrice per week for 6-10 weeks of age, and the therapeutic effects in the SMG were assessed at the end of 10 weeks of age. NOD/ShiLtJ mice treated with HS showed attenuated salivary gland inflammation with reduced B-cell infiltration, germinal center formation and CXCR5 expression. These findings suggest that SDC-1 plays a pivotal role in the pathogenesis of SjD by binding to CXCL13 through the HS chain.
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Affiliation(s)
- Nan Young Lee
- Department of Clinical Pathology, School of Medicine, Kyungpook National University, Daegu 41405, Republic of Korea
| | - Hirut Yadeta Ture
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41405, Republic of Korea
| | - Eun Ju Lee
- Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu 41199, Republic of Korea
| | - Ji Ae Jang
- Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu 41199, Republic of Korea
| | - Gunwoo Kim
- Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu 41199, Republic of Korea
| | - Eon Jeong Nam
- Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41405, Republic of Korea
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5
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Jafri M, Li L, Liang B, Luo M. The Effect of Heparin and Other Exogenous Glycosaminoglycans (GAGs) in Reducing IL-1β-Induced Pro-Inflammatory Cytokine IL-8 and IL-6 mRNA Expression and the Potential Role for Reducing Inflammation. Pharmaceuticals (Basel) 2024; 17:371. [PMID: 38543157 PMCID: PMC10976005 DOI: 10.3390/ph17030371] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 11/12/2024] Open
Abstract
Glycosaminoglycans (GAGs) are long linear polysaccharides found in every mammalian tissue. Previously thought only to be involved in cellular structure or hydration, GAGs are now known to be involved in cell signaling and protein modulation in cellular adhesion, growth, proliferation, and anti-coagulation. In this study, we showed that GAGs have an inhibitory effect on the IL-1β-stimulated mRNA expression of IL-6 and IL-8. Exogenous heparin (p < 0.0001), heparan (p < 0.0001), chondroitin (p < 0.049), dermatan (p < 0.0027), and hyaluronan (p < 0.0005) significantly reduced the IL-1β-induced IL-8 mRNA expression in HeLa cells. Exogenous heparin (p < 0.0001), heparan (p < 0.0001), and dermatan (p < 0.0027) also significantly reduced IL-1β-induced IL-6 mRNA expression in HeLa cells, but exogenous chondroitin and hyaluronan had no significant effect. The exogenous GAGs may reduce the transcription of these inflammatory cytokines through binding to TILRR, a co-receptor of IL-1R1, and block/reduce the interactions of TILRR with IL-1R1.
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Affiliation(s)
- Murtaza Jafri
- Faculty of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada;
| | - Lin Li
- National Microbiology Laboratory, Winnipeg, MB R3E 3R2, Canada; (L.L.); (B.L.)
| | - Binhua Liang
- National Microbiology Laboratory, Winnipeg, MB R3E 3R2, Canada; (L.L.); (B.L.)
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Ma Luo
- National Microbiology Laboratory, Winnipeg, MB R3E 3R2, Canada; (L.L.); (B.L.)
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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6
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Dürig JN, Schulze C, Bosse M, Penk A, Huster D, Keller S, Rademann J. Dimerization and Crowding in the Binding of Interleukin 8 to Dendritic Glycosaminoglycans as Artificial Proteoglycans. Chemistry 2024; 30:e202302758. [PMID: 38010268 DOI: 10.1002/chem.202302758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023]
Abstract
The interactions of glycosaminoglycans (GAG) with proteins of the extracellular matrix govern and regulate complex physiological functions including cellular growth, immune response, and inflammation. Repetitive presentation of GAG binding motifs, as found in native proteoglycans, might enhance GAG-protein binding through multivalent interactions. Here, we report the chemical synthesis of dendritic GAG oligomers constructed of nonasulfated hyaluronan tetrasaccharides for investigating the binding of the protein chemokine interleukin 8 (IL-8) to artificial, well-defined proteoglycan architectures. Binding of mutant monomeric and native dimerizable IL-8 was investigated by NMR spectroscopy and isothermal titration calorimetry. Dendritic oligomerization of GAG increased the binding affinity of both monomeric and dimeric IL-8. Monomeric IL-8 bound to monomeric and dimeric GAG with KD values of 7.3 and 0.108 μM, respectively. The effect was less pronounced for dimerizable wild-type IL-8, for which GAG dimerization improved the affinity from 34 to 5 nM. Binding of dimeric IL-8 to oligomeric GAG was limited by steric crowding effects, strongly reducing the affinity of subsequent binding events. In conclusion, the strongest effect of GAG oligomerization was the amplified binding of IL-8 monomers, which might concentrate monomeric protein in the extracellular matrix and thus promote protein dimerization under physiological conditions.
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Affiliation(s)
- Jan-Niklas Dürig
- Institute of Pharmacy - Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany) Corresponding author
| | - Christian Schulze
- Institute of Medical Physics and Biophysics, Leipzig University, Härtelstr. 16/18, 04107, Leipzig, Germany
| | - Mathias Bosse
- Institute of Medical Physics and Biophysics, Leipzig University, Härtelstr. 16/18, 04107, Leipzig, Germany
| | - Anja Penk
- Institute of Medical Physics and Biophysics, Leipzig University, Härtelstr. 16/18, 04107, Leipzig, Germany
| | - Daniel Huster
- Institute of Medical Physics and Biophysics, Leipzig University, Härtelstr. 16/18, 04107, Leipzig, Germany
| | - Sandro Keller
- Biophysics, Institute of Molecular Biosciences (IMB), NAWI Graz, Field of Excellence BioHealth, BioTechMed-Graz, University of Graz, Humboldtstr. 50/III, 8010, Graz, Austria
| | - Jörg Rademann
- Institute of Pharmacy - Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany) Corresponding author
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7
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Dalmau Gasull A, Glavan M, Samawar SKR, Kapupara K, Kelk J, Rubio M, Fumagalli S, Sorokin L, Vivien D, Prinz M. The niche matters: origin, function and fate of CNS-associated macrophages during health and disease. Acta Neuropathol 2024; 147:37. [PMID: 38347231 PMCID: PMC10861620 DOI: 10.1007/s00401-023-02676-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/13/2023] [Accepted: 12/22/2023] [Indexed: 02/15/2024]
Abstract
There are several cellular and acellular structural barriers associated with the brain interfaces, which include the dura, the leptomeninges, the perivascular space and the choroid plexus epithelium. Each structure is enriched by distinct myeloid populations, which mainly originate from erythromyeloid precursors (EMP) in the embryonic yolk sac and seed the CNS during embryogenesis. However, depending on the precise microanatomical environment, resident myeloid cells differ in their marker profile, turnover and the extent to which they can be replenished by blood-derived cells. While some EMP-derived cells seed the parenchyma to become microglia, others engraft the meninges and become CNS-associated macrophages (CAMs), also referred to as border-associated macrophages (BAMs), e.g., leptomeningeal macrophages (MnMΦ). Recent data revealed that MnMΦ migrate into perivascular spaces postnatally where they differentiate into perivascular macrophages (PvMΦ). Under homeostatic conditions in pathogen-free mice, there is virtually no contribution of bone marrow-derived cells to MnMΦ and PvMΦ, but rather to macrophages of the choroid plexus and dura. In neuropathological conditions in which the blood-brain barrier is compromised, however, an influx of bone marrow-derived cells into the CNS can occur, potentially contributing to the pool of CNS myeloid cells. Simultaneously, resident CAMs may also proliferate and undergo transcriptional and proteomic changes, thereby, contributing to the disease outcome. Thus, both resident and infiltrating myeloid cells together act within their microenvironmental niche, but both populations play crucial roles in the overall disease course. Here, we summarize the current understanding of the sources and fates of resident CAMs in health and disease, and the role of the microenvironment in influencing their maintenance and function.
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Affiliation(s)
- Adrià Dalmau Gasull
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Martina Glavan
- Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), 14000, Caen, France
- Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, USA
| | - Sai K Reddy Samawar
- Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre (CIMIC), University of Münster, Münster, Germany
| | - Kishan Kapupara
- Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre (CIMIC), University of Münster, Münster, Germany
| | - Joe Kelk
- Laboratory of Stroke and Vascular Dysfunctions, Department of Acute Brain and Cardiovascular Injury, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy
| | - Marina Rubio
- Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), 14000, Caen, France
| | - Stefano Fumagalli
- Laboratory of Stroke and Vascular Dysfunctions, Department of Acute Brain and Cardiovascular Injury, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy
| | - Lydia Sorokin
- Institute of Physiological Chemistry and Pathobiochemistry and Cells in Motion Interfaculty Centre (CIMIC), University of Münster, Münster, Germany
| | - Denis Vivien
- Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), 14000, Caen, France
- Department of Clinical Research, Caen-Normandie University Hospital, CHU, Avenue de La Côte de Nacre, Caen, France
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- Signalling Research Centres BIOSS and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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8
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Kunnathattil M, Rahul P, Skaria T. Soluble vascular endothelial glycocalyx proteoglycans as potential therapeutic targets in inflammatory diseases. Immunol Cell Biol 2024; 102:97-116. [PMID: 37982607 DOI: 10.1111/imcb.12712] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 11/21/2023]
Abstract
Reducing the activity of cytokines and leukocyte extravasation is an emerging therapeutic strategy to limit tissue-damaging inflammatory responses and restore immune homeostasis in inflammatory diseases. Proteoglycans embedded in the vascular endothelial glycocalyx, which regulate the activity of cytokines to restrict the inflammatory response in physiological conditions, are proteolytically cleaved in inflammatory diseases. Here we critically review the potential of proteolytically shed, soluble vascular endothelial glycocalyx proteoglycans to modulate pathological inflammatory responses. Soluble forms of the proteoglycans syndecan-1, syndecan-3 and biglycan exert beneficial anti-inflammatory effects by the removal of chemokines, suppression of proinflammatory cytokine expression and leukocyte migration, and induction of autophagy of proinflammatory M1 macrophages. By contrast, soluble versikine and decorin enhance proinflammatory responses by increasing inflammatory cytokine synthesis and leukocyte migration. Endogenous syndecan-2 and mimecan exert proinflammatory effects, syndecan-4 and perlecan mediate beneficial anti-inflammatory effects and glypican regulates Hh and Wnt signaling pathways involved in systemic inflammatory responses. Taken together, targeting the vascular endothelial glycocalyx-derived, soluble syndecan-1, syndecan-2, syndecan-3, syndecan-4, biglycan, versikine, mimecan, perlecan, glypican and decorin might be a potential therapeutic strategy to suppress overstimulated cytokine and leukocyte responses in inflammatory diseases.
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Affiliation(s)
- Maneesha Kunnathattil
- Department of Zoology, Government College Madappally, University of Calicut, Calicut, Kerala, India
| | - Pedapudi Rahul
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
| | - Tom Skaria
- School of Biotechnology, National Institute of Technology Calicut, Calicut, Kerala, India
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9
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Tanino Y. Roles of extracellular matrix in lung diseases. Fukushima J Med Sci 2024; 70:1-9. [PMID: 38267030 PMCID: PMC10867433 DOI: 10.5387/fms.2023-07] [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: 02/20/2023] [Accepted: 11/20/2023] [Indexed: 01/26/2024] Open
Abstract
Extracellular matrix (ECM) is a non-cellular constituent found in all tissues and organs. Although ECM was previously recognized as a mere "molecular glue" that supports the tissue structure of organs such as the lungs, it has recently been reported that ECM has important biological activities for tissue morphogenesis, inflammation, wound healing, and tumor progression. Proteoglycans are the main constituent of ECM, with growing evidence that proteoglycans and their associated glycosaminoglycans play important roles in the pathogenesis of several diseases. However, their roles in the lungs are incompletely understood. Leukocyte migration into the lung is one of the main aspects involved in the pathogenesis of several lung diseases. Glycosaminoglycans bind to chemokines and their interaction fine-tunes leukocyte migration into the affected organs. This review focuses on the role chemokine and glycosaminoglycan interactions in neutrophil migration into the lung. Furthermore, this review presents the role of proteoglycans such as syndecan, versican, and hyaluronan in inflammatory and fibrotic lung diseases.
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Affiliation(s)
- Yoshinori Tanino
- Department of Pulmonary Medicine, Fukushima Medical University School of Medicine
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10
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Hayden MR. The Brain Endothelial Cell Glycocalyx Plays a Crucial Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus. Life (Basel) 2023; 13:1955. [PMID: 37895337 PMCID: PMC10608474 DOI: 10.3390/life13101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/07/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may be considered as the first barrier of a tripartite blood-brain barrier (BBB) consisting of (1) ecGCx; (2) BECs; and (3) an extravascular compartment of pericytes, the extracellular matrix, and perivascular astrocytes. Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally derived leukocytes into the perivascular spaces (PVS) which result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the fifth review of a quintet series that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids, and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are increasingly being regarded as a marker of cerebrovascular and neurodegenerative pathology.
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Affiliation(s)
- Melvin R Hayden
- Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65211, USA
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11
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Feng K, Wang K, Zhou Y, Xue H, Wang F, Jin H, Zhao W. Non-Anticoagulant Activities of Low Molecular Weight Heparins-A Review. Pharmaceuticals (Basel) 2023; 16:1254. [PMID: 37765064 PMCID: PMC10537022 DOI: 10.3390/ph16091254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/23/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Low molecular weight heparins (LMWHs) are derived from heparin through chemical or enzymatic cleavage with an average molecular weight (Mw) of 2000-8000 Da. They exhibit more selective activities and advantages over heparin, causing fewer side effects, such as bleeding and heparin-induced thrombocytopenia. Due to different preparation methods, LMWHs have diverse structures and extensive biological activities. In this review, we describe the basic preparation methods in this field and compare the main principles and advantages of these specific methods in detail. Importantly, we focus on the non-anticoagulant pharmacological effects of LMWHs and their conjugates, such as preventing glycocalyx shedding, anti-inflammatory, antiviral infection, anti-fibrosis, inhibiting angiogenesis, inhibiting cell adhesion and improving endothelial function. LMWHs are effective in various diseases at the animal level, including cancer, some viral diseases, fibrotic diseases, and obstetric diseases. Finally, we briefly summarize their usage and potential applications in the clinic to promote the development and utilization of LMWHs.
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Affiliation(s)
- Ke Feng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
| | - Kaixuan Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
| | - Yu Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
| | - Haoyu Xue
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
| | - Fang Wang
- Department of Stomatology, Tianjin Nankai Hospital, 6 Changjiang Road, Nankai District, Tianjin 300100, China
| | - Hongzhen Jin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
| | - Wei Zhao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Jinnan District, Tianjin 300350, China; (K.F.); (K.W.); (Y.Z.); (H.X.); (W.Z.)
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12
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Gschwandtner M, Gammage AN, Deligne C, Mies LFM, Domaingo A, Murdamoothoo D, Loustau T, Schwenzer A, Derler R, Carapito R, Koch M, Mörgelin M, Orend G, Kungl AJ, Midwood KS. Investigating Chemokine-Matrix Networks in Breast Cancer: Tenascin-C Sets the Tone for CCL2. Int J Mol Sci 2023; 24:8365. [PMID: 37176074 PMCID: PMC10179296 DOI: 10.3390/ijms24098365] [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: 03/31/2023] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Bidirectional dialogue between cellular and non-cellular components of the tumor microenvironment (TME) drives cancer survival. In the extracellular space, combinations of matrix molecules and soluble mediators provide external cues that dictate the behavior of TME resident cells. Often studied in isolation, integrated cues from complex tissue microenvironments likely function more cohesively. Here, we study the interplay between the matrix molecule tenascin-C (TNC) and chemokine CCL2, both elevated in and associated with the progression of breast cancer and playing key roles in myeloid immune responses. We uncover a correlation between TNC/CCL2 tissue levels in HER2+ breast cancer and examine the physical and functional interactions of these molecules in a murine disease model with tunable TNC levels and in in vitro cellular and cell-free models. TNC supported sustained CCL2 synthesis, with chemokine binding to TNC via two distinct domains. TNC dominated the behavior of tumor-resident myeloid cells; CCL2 did not impact macrophage survival/activation whilst TNC facilitated an immune suppressive macrophage phenotype that was not dependent on or altered by CCL2 co-expression. Together, these data map new binding partners within the TME and demonstrate that whilst the matrix exerts transcriptional control over the chemokine, each plays a distinct role in subverting anti-tumoral immunity.
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Affiliation(s)
| | - Anís N. Gammage
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Claire Deligne
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Linda F. M. Mies
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Alissa Domaingo
- Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria
| | - Devardarssen Murdamoothoo
- INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 67091 Strasbourg, France
- University of Strasbourg, 67091 Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67091 Strasbourg, France
- INSERM U1109, The Tumor Microenvironment Group, 67091 Strasbourg, France
| | - Thomas Loustau
- INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 67091 Strasbourg, France
- University of Strasbourg, 67091 Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67091 Strasbourg, France
- INSERM U1109, The Tumor Microenvironment Group, 67091 Strasbourg, France
| | - Anja Schwenzer
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
| | - Rupert Derler
- Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria
| | - Raphael Carapito
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67091 Strasbourg, France
- Laboratoire d’ImmunoRhumatologie Moléculaire, GENOMAX Platform, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, ITI TRANSPLANTEX NG, Université de Strasbourg, 67091 Strasbourg, France
| | - Manuel Koch
- Institute for Dental Research and Oral, Musculoskeletal Research, Center for Biochemistry, University of Cologne, 50931 Cologne, Germany
| | | | - Gertraud Orend
- INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 67091 Strasbourg, France
- University of Strasbourg, 67091 Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67091 Strasbourg, France
- INSERM U1109, The Tumor Microenvironment Group, 67091 Strasbourg, France
| | - Andreas J. Kungl
- Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria
| | - Kim S. Midwood
- Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
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13
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Shute JK. Heparin, Low Molecular Weight Heparin, and Non-Anticoagulant Derivatives for the Treatment of Inflammatory Lung Disease. Pharmaceuticals (Basel) 2023; 16:ph16040584. [PMID: 37111341 PMCID: PMC10141002 DOI: 10.3390/ph16040584] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route.
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Affiliation(s)
- Janis Kay Shute
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2UP, UK
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14
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Parween F, Singh SP, Zhang HH, Kathuria N, Otaizo-Carrasquero FA, Shamsaddini A, Gardina PJ, Ganesan S, Kabat J, Lorenzi HA, Myers TG, Farber JM. Chemokine positioning determines mutually exclusive roles for their receptors in extravasation of pathogenic human T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.25.525561. [PMID: 36789428 PMCID: PMC9928044 DOI: 10.1101/2023.01.25.525561] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Pro-inflammatory T cells co-express multiple chemokine receptors, but the distinct functions of individual receptors on these cells are largely unknown. Human Th17 cells uniformly express the chemokine receptor CCR6, and we discovered that the subgroup of CD4+CCR6+ cells that co-express CCR2 possess a pathogenic Th17 signature, can produce inflammatory cytokines independent of TCR activation, and are unusually efficient at transendothelial migration (TEM). The ligand for CCR6, CCL20, was capable of binding to activated endothelial cells (ECs) and inducing firm arrest of CCR6+CCR2+ cells under conditions of flow - but CCR6 could not mediate TEM. By contrast, CCL2 and other ligands for CCR2, despite being secreted from both luminal and basal sides of ECs, failed to bind to the EC surfaces - and CCR2 could not mediate arrest. Nonetheless, CCR2 was required for TEM. To understand if CCR2's inability to mediate arrest was due solely to an absence of EC-bound ligands, we generated a CCL2-CXCL9 chimeric chemokine that could bind to the EC surface. Although display of CCL2 on the ECs did indeed lead to CCR2-mediated arrest of CCR6+CCR2+ cells, activating CCR2 with surface-bound CCL2 blocked TEM. We conclude that mediating arrest and TEM are mutually exclusive activities of chemokine receptors and/or their ligands that depend, respectively, on chemokines that bind to the EC luminal surfaces versus non-binding chemokines that form transendothelial gradients under conditions of flow. Our findings provide fundamental insights into mechanisms of lymphocyte extravasation and may lead to novel strategies to block or enhance their migration into tissue.
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Affiliation(s)
- Farhat Parween
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Satya P. Singh
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Hongwei H Zhang
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Nausheen Kathuria
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Francisco A. Otaizo-Carrasquero
- Research Technologies Branch, Genomic Technologies, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Amirhossein Shamsaddini
- Research Technologies Branch, Genomic Technologies, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Paul J. Gardina
- Research Technologies Branch, Genomic Technologies, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Sundar Ganesan
- Research Technologies Branch, Biological Imaging, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Juraj Kabat
- Research Technologies Branch, Biological Imaging, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Hernan A. Lorenzi
- Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Timothy G. Myers
- Research Technologies Branch, Genomic Technologies, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
| | - Joshua M. Farber
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda MD 20892, USA
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15
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Ma Y, Chen H. Analysis of Chemokine-to-GAG Interactions in Model of Donor Renal Allograft Transplant. Methods Mol Biol 2023; 2597:25-38. [PMID: 36374412 DOI: 10.1007/978-1-0716-2835-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Binding of chemokines to glycosaminoglycans (GAGs) is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct immune cell responses initiating local leukocyte chemotaxis into damaged or transplanted tissues. The interaction between chemokines and GAGs is an important factor affecting transplant rejection, and blocking the interactions between chemokines and GAGs can significantly reduce acute rejection after transplantation. Here, we investigated the interaction between chemokines and GAGs by establishing a mouse model of acute rejection after kidney transplantation.
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Affiliation(s)
- Yanlin Ma
- The Second Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Hao Chen
- Department of Tumor Center, Lanzhou University Second Hospital, Lanzhou, China.
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16
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Chemistry and Function of Glycosaminoglycans in the Nervous System. ADVANCES IN NEUROBIOLOGY 2023; 29:117-162. [DOI: 10.1007/978-3-031-12390-0_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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17
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Impact of Sulfated Hyaluronan on Bone Metabolism in Diabetic Charcot Neuroarthropathy and Degenerative Arthritis. Int J Mol Sci 2022; 23:ijms232315146. [PMID: 36499493 PMCID: PMC9737841 DOI: 10.3390/ijms232315146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022] Open
Abstract
Bone in diabetes mellitus is characterized by an altered microarchitecture caused by abnormal metabolism of bone cells. Together with diabetic neuropathy, this is associated with serious complications including impaired bone healing culminating in complicated fractures and dislocations, especially in the lower extremities, so-called Charcot neuroarthropathy (CN). The underlying mechanisms are not yet fully understood, and treatment of CN is challenging. Several in vitro and in vivo investigations have suggested positive effects on bone regeneration by modifying biomaterials with sulfated glycosaminoglycans (sGAG). Recent findings described a beneficial effect of sGAG for bone healing in diabetic animal models compared to healthy animals. We therefore aimed at studying the effects of low- and high-sulfated hyaluronan derivatives on osteoclast markers as well as gene expression patterns of osteoclasts and osteoblasts from patients with diabetic CN compared to non-diabetic patients with arthritis at the foot and ankle. Exposure to sulfated hyaluronan (sHA) derivatives reduced the exaggerated calcium phosphate resorption as well as the expression of genes associated with bone resorption in both groups, but more pronounced in patients with CN. Moreover, sHA derivatives reduced the release of pro-inflammatory cytokines in osteoclasts of patients with CN. The effects of sHA on osteoblasts differed only marginally between patients with CN and non-diabetic patients with arthritis. These results suggest balancing effects of sHA on osteoclastic bone resorption parameters in diabetes.
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18
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Wu KCH, He Q, Bennett AN, Li J, Chan KHK. Shared genetic mechanism between type 2 diabetes and COVID-19 using pathway-based association analysis. Front Genet 2022; 13:1063519. [PMID: 36482905 PMCID: PMC9724785 DOI: 10.3389/fgene.2022.1063519] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/07/2022] [Indexed: 08/10/2023] Open
Abstract
Recent studies have shown that, compared with healthy individuals, patients with type 2 diabetes (T2D) suffer a higher severity and mortality of COVID-19. When infected with this retrovirus, patients with T2D are more likely to face severe complications from cytokine storms and be admitted to high-dependency or intensive care units. Some COVID-19 patients are known to suffer from various forms of acute respiratory distress syndrome and have a higher mortality risk due to extreme activation of inflammatory cascades. Using a conditional false discovery rate statistical framework, an independent genome-wide association study data on individuals presenting with T2D (N = 62,892) and COVID-19 (N = 38,984) were analysed. Genome-wide association study data from 2,343,084 participants were analysed and a significant positive genetic correlation between T2D and COVID-19 was observed (T2D: r for genetic = 0.1511, p-value = 0.01). Overall, 2 SNPs (rs505922 and rs3924604) shared in common between T2D and COVID-19 were identified. Functional analyses indicated that the overlapping loci annotated into the ABO and NUS1 genes might be implicated in several key metabolic pathways. A pathway association analysis identified two common pathways within T2D and COVID-19 pathogenesis, including chemokines and their respective receptors. The gene identified from the pathway analysis (CCR2) was also found to be highly expressed in blood tissue via the GTEx database. To conclude, this study reveals that certain chemokines and their receptors, which are directly involved in the genesis of cytokine storms, may lead to exacerbated hyperinflammation in T2D patients infected by COVID-19.
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Affiliation(s)
- Kevin Chun Hei Wu
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qian He
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Adam N. Bennett
- Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Jie Li
- Global Health Research Centre, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kei Hang Katie Chan
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Epidemiology and Center for Global Cardiometabolic Health, Brown University, Providence, RI, United States
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19
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Yaylaci S, Guler MO, Tekinay AB. Sulfated GAG mimetic peptide nanofibers enhance chondrogenic differentiation of mesenchymal stem cells in 3D in vitro models. Regen Biomater 2022; 10:rbac084. [PMID: 36683737 PMCID: PMC9847523 DOI: 10.1093/rb/rbac084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/27/2022] [Accepted: 10/08/2022] [Indexed: 11/09/2022] Open
Abstract
Articular cartilage, which is exposed to continuous repetitive compressive stress, has limited self-healing capacity in the case of trauma. Thus, it is crucial to develop new treatment options for the effective regeneration of the cartilage tissue. Current cellular therapy treatment options are microfracture and autologous chondrocyte implantation; however, these treatments induce the formation of fibrous cartilage, which degenerates over time, rather than functional hyaline cartilage tissue. Tissue engineering studies using biodegradable scaffolds and autologous cells are vital for developing an effective long-term treatment option. 3D scaffolds composed of glycosaminoglycan-like peptide nanofibers are synthetic, bioactive, biocompatible, and biodegradable and trigger cell-cell interactions that enhance chondrogenic differentiation of cells without using any growth factors. We showed differentiation of mesenchymal stem cells into chondrocytes in both 2D and 3D culture, which produce a functional cartilage extracellular matrix, employing bioactive cues integrated into the peptide nanofiber scaffold without adding exogenous growth factors.
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Affiliation(s)
| | - Mustafa O Guler
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
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20
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Oliveira THC, Vanheule V, Vandendriessche S, Poosti F, Teixeira MM, Proost P, Gouwy M, Marques PE. The GAG-Binding Peptide MIG30 Protects against Liver Ischemia-Reperfusion in Mice. Int J Mol Sci 2022; 23:ijms23179715. [PMID: 36077113 PMCID: PMC9456047 DOI: 10.3390/ijms23179715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 11/24/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) drives graft rejection and is the main cause of mortality after liver transplantation. During IRI, an intense inflammatory response marked by chemokine production and neutrophil recruitment occurs. However, few strategies are available to restrain this excessive response. Here, we aimed to interfere with chemokine function during IRI in order to disrupt neutrophil recruitment to the injured liver. For this, we utilized a potent glycosaminoglycan (GAG)-binding peptide containing the 30 C-terminal amino acids of CXCL9 (MIG30) that is able to inhibit the binding of chemokines to GAGs in vitro. We observed that mice subjected to IRI and treated with MIG30 presented significantly lower liver injury and dysfunction as compared to vehicle-treated mice. Moreover, the levels of chemokines CXCL1, CXCL2 and CXCL6 and of proinflammatory cytokines TNF-α and IL-6 were significantly reduced in MIG30-treated mice. These events were associated with a marked inhibition of neutrophil recruitment to the liver during IRI. Lastly, we observed that MIG30 is unable to affect leukocytes directly nor to alter the stimulation by either CXCL8 or lipopolysaccharide (LPS), suggesting that its protective properties derive from its ability to inhibit chemokine activity in vivo. We conclude that MIG30 holds promise as a strategy to treat liver IRI and inflammation.
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Affiliation(s)
- Thiago Henrique Caldeira Oliveira
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Vincent Vanheule
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Sofie Vandendriessche
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Fariba Poosti
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Mauro Martins Teixeira
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
| | - Pedro Elias Marques
- Laboratory of Molecular Immunology, Department of Microbiology, Rega Institute, Immunology and Transplantation, KU Leuven, 3000 Leuven, Belgium
- Correspondence:
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21
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Tang F, Brune JE, Chang MY, Reeves SR, Altemeier WA, Frevert CW. Defining the versican interactome in lung health and disease. Am J Physiol Cell Physiol 2022; 323:C249-C276. [PMID: 35649251 PMCID: PMC9291419 DOI: 10.1152/ajpcell.00162.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/17/2022] [Indexed: 11/22/2022]
Abstract
The extracellular matrix (ECM) imparts critical mechanical and biochemical information to cells in the lungs. Proteoglycans are essential constituents of the ECM and play a crucial role in controlling numerous biological processes, including regulating cellular phenotype and function. Versican, a chondroitin sulfate proteoglycan required for embryonic development, is almost absent from mature, healthy lungs and is reexpressed and accumulates in acute and chronic lung disease. Studies using genetically engineered mice show that the versican-enriched matrix can be pro- or anti-inflammatory depending on the cellular source or disease process studied. The mechanisms whereby versican develops a contextual ECM remain largely unknown. The primary goal of this review is to provide an overview of the interaction of versican with its many binding partners, the "versican interactome," and how through these interactions, versican is an integrator of complex extracellular information. Hopefully, the information provided in this review will be used to develop future studies to determine how versican and its binding partners can develop contextual ECMs that control select biological processes. Although this review focuses on versican and the lungs, what is described can be extended to other proteoglycans, tissues, and organs.
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Affiliation(s)
- Fengying Tang
- Center for Lung Biology, The University of Washington at South Lake Union, Seattle, Washington
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Jourdan E Brune
- Center for Lung Biology, The University of Washington at South Lake Union, Seattle, Washington
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Mary Y Chang
- Center for Lung Biology, The University of Washington at South Lake Union, Seattle, Washington
- Department of Comparative Medicine, University of Washington, Seattle, Washington
| | - Stephen R Reeves
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington
- Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Washington, Seattle, Washington
| | - William A Altemeier
- Center for Lung Biology, The University of Washington at South Lake Union, Seattle, Washington
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington
| | - Charles W Frevert
- Center for Lung Biology, The University of Washington at South Lake Union, Seattle, Washington
- Department of Comparative Medicine, University of Washington, Seattle, Washington
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington
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22
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Lauth LM, Voigt B, Bhatia T, Machner L, Balbach J, Ott M. Heparin promotes rapid fibrillation of the basic Parathyroid Hormone at physiological pH. FEBS Lett 2022; 596:2928-2939. [PMID: 35903816 DOI: 10.1002/1873-3468.14455] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 06/14/2022] [Accepted: 07/09/2022] [Indexed: 11/06/2022]
Abstract
In acidic secretory granules of mammalian cells, peptide hormones including the parathyroid hormone (PTH) are presumably stored in the form of functional amyloid fibrils. Mature PTH, however, is considerably positively charged in acidic environments, a condition known to impede unassisted self-aggregation into fibrils. Here, we studied the role of the polyanion heparin on promoting fibril formation of PTH. Employing ITC, CD spectroscopy, NMR, SAXS and fluorescence-based assays we could demonstrate that heparin binds PTH with submicromolar affinity and facilitates its conversion into fibrillar seeds, enabling rapid formation of amyloid fibrils under acidic conditions. In absence of heparin, PTH remained in a soluble monomeric state. We suspect that heparin-like surfaces are required in vivo to convert PTH efficiently into fibrillar deposits.
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Affiliation(s)
- Luca M Lauth
- Department of Biochemistry and Biotechnology, Martin-Luther-University, Halle-Wittenberg, Halle, Germany
| | - Bruno Voigt
- Department of Biophysics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Twinkle Bhatia
- Department of Biochemistry and Biotechnology, Martin-Luther-University, Halle-Wittenberg, Halle, Germany
| | - Lisa Machner
- Department of Molecular Medicine, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Jochen Balbach
- Department of Biophysics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Maria Ott
- Department of Biochemistry and Biotechnology, Martin-Luther-University, Halle-Wittenberg, Halle, Germany
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23
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Caird R, Williamson M, Yusuf A, Gogoi D, Casey M, McElvaney NG, Reeves EP. Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease. Int J Mol Sci 2022; 23:ijms23126400. [PMID: 35742845 PMCID: PMC9224208 DOI: 10.3390/ijms23126400] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/02/2022] [Accepted: 06/05/2022] [Indexed: 12/10/2022] Open
Abstract
In the lung, glycosaminoglycans (GAGs) are dispersed in the extracellular matrix (ECM) occupying the interstitial space between the capillary endothelium and the alveolar epithelium, in the sub-epithelial tissue and in airway secretions. In addition to playing key structural roles, GAGs contribute to a number of physiologic processes ranging from cell differentiation, cell adhesion and wound healing. Cytokine and chemokine–GAG interactions are also involved in presentation of inflammatory molecules to respective receptors leading to immune cell migration and airway infiltration. More recently, pathophysiological roles of GAGs have been described. This review aims to discuss the biological roles and molecular interactions of GAGs, and their impact in the pathology of chronic airway diseases, such as cystic fibrosis and chronic obstructive pulmonary disease. Moreover, the role of GAGs in respiratory disease has been heightened by the current COVID-19 pandemic. This review underlines the essential need for continued research aimed at exploring the contribution of GAGs in the development of inflammation, to provide a better understanding of their biological impact, as well as leads in the development of new therapeutic agents.
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24
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Milusev A, Rieben R, Sorvillo N. The Endothelial Glycocalyx: A Possible Therapeutic Target in Cardiovascular Disorders. Front Cardiovasc Med 2022; 9:897087. [PMID: 35647072 PMCID: PMC9136230 DOI: 10.3389/fcvm.2022.897087] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022] Open
Abstract
The physiological, anti-inflammatory, and anti-coagulant properties of endothelial cells (ECs) rely on a complex carbohydrate-rich layer covering the luminal surface of ECs, called the glycocalyx. In a range of cardiovascular disorders, glycocalyx shedding causes endothelial dysfunction and inflammation, underscoring the importance of glycocalyx preservation to avoid disease initiation and progression. In this review we discuss the physiological functions of the glycocalyx with particular focus on how loss of endothelial glycocalyx integrity is linked to cardiovascular risk factors, like hypertension, aging, diabetes and obesity, and contributes to the development of thrombo-inflammatory conditions. Finally, we consider the role of glycocalyx components in regulating inflammatory responses and discuss possible therapeutic interventions aiming at preserving or restoring the endothelial glycocalyx and therefore protecting against cardiovascular disease.
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Affiliation(s)
- Anastasia Milusev
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Robert Rieben
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nicoletta Sorvillo
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- *Correspondence: Nicoletta Sorvillo
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25
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Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination. Int J Mol Sci 2022; 23:ijms23063338. [PMID: 35328761 PMCID: PMC8955234 DOI: 10.3390/ijms23063338] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/03/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes.
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26
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Gao Y, Qiu Z, Liu L, Li M, Xu B, Yu D, Qi D, Wu J. Multifunctional fibrous wound dressings for refractory wound healing. JOURNAL OF POLYMER SCIENCE 2022. [DOI: 10.1002/pol.20220008] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yujie Gao
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
| | - Zhiye Qiu
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
| | - Lei Liu
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
| | - Mengmeng Li
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
| | - Bingjie Xu
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
| | - Dan Yu
- Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China
| | - Dongming Qi
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
- Zhejiang Provincial Engineering Research Center for Green and Low‐carbon Dyeing & Finishing Zhejiang Sci‐Tech University Hangzhou China
| | - Jindan Wu
- MOE Key Laboratory of Advanced Textile Materials & Manufacturing Technology Zhejiang Sci‐Tech University Hangzhou China
- Zhejiang Provincial Engineering Research Center for Green and Low‐carbon Dyeing & Finishing Zhejiang Sci‐Tech University Hangzhou China
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27
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Dutta AK, Sepuru KM, Rösgen J, Rajarathnam K. Characterizing Thermodynamics of Protein-Glycosaminoglycan Interactions Using Isothermal Titration Calorimetry. Methods Mol Biol 2022; 2303:307-317. [PMID: 34626389 DOI: 10.1007/978-1-0716-1398-6_25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
It has now become increasingly clear that a complete atomic description of how biomacromolecules recognize each other requires knowledge not only of the structures of the complexes but also of how kinetics and thermodynamics drive the binding process. In particular, such knowledge is lacking for protein-glycosaminoglycan (GAG) complexes. Isothermal titration calorimetry (ITC) is the only technique that can provide all of the thermodynamic parameters-enthalpy, entropy, free energy (binding constant), and stoichiometry-from a single experiment. Here we describe different factors that must be taken into consideration in carrying out ITC titrations to obtain meaningful thermodynamic data of protein-GAG interactions.
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Affiliation(s)
- Amit K Dutta
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Krishna Mohan Sepuru
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Jörg Rösgen
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA
| | - Krishna Rajarathnam
- Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
- Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, TX, USA.
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28
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Brunori F, Padhi DK, Alshanski I, Freyse J, Dürig JN, Penk A, Vaccaro L, Hurevich M, Rademann J, Yitzchaik S. Sulfation Pattern Dependent Iron(III) Mediated Interleukin-8 Glycan Binding. Chembiochem 2021; 23:e202100552. [PMID: 34851004 DOI: 10.1002/cbic.202100552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/01/2021] [Indexed: 12/30/2022]
Abstract
Cytokines such as interleukin-8 activate the immune system during infection and interact with sulfated glycosaminoglycans with specific sulfation patterns. In some cases, these interactions are mediated by metal ion binding which can be used to tune surface-based glycan-protein interactions. We evaluated the effect of both hyaluronan sulfation degree and Fe3+ on interleukin-8 binding by electrochemical impedance spectroscopy and surface characterizations. Our results show that sulfation degree and metal ion interactions have a synergistic effect in tuning the electrochemical response of the glycated surfaces to the cytokine.
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Affiliation(s)
- Francesco Brunori
- Institute of Chemistry and Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904, Israel.,Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica, Biologiae Biotecnologie, Università di Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy
| | - Deepak Kumar Padhi
- Institute of Chemistry and Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904, Israel
| | - Israel Alshanski
- Institute of Chemistry and Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904, Israel
| | - Joanna Freyse
- Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany
| | - Jan-Niklas Dürig
- Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany
| | - Anja Penk
- Institute of Medical Physics and Biophysics, Leipzig University, Medical Faculty, Härtelstraße 16/18, 04107, Leipzig, Germany
| | - Luigi Vaccaro
- Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica, Biologiae Biotecnologie, Università di Perugia, Via Elce di Sotto 8, 06123, Perugia, Italy
| | - Mattan Hurevich
- Institute of Chemistry and Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904, Israel
| | - Jörg Rademann
- Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Strasse 2+4, Berlin, 14195, Germany
| | - Shlomo Yitzchaik
- Institute of Chemistry and Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Safra Campus, Givat Ram, Jerusalem, 91904, Israel
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29
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Williamson M, Casey M, Gabillard-Lefort C, Alharbi A, Teo YQJ, McElvaney NG, Reeves EP. Current evidence on the effect of highly effective CFTR modulation on interleukin-8 in cystic fibrosis. Expert Rev Respir Med 2021; 16:43-56. [PMID: 34726115 DOI: 10.1080/17476348.2021.2001333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Cystic fibrosis (CF) is a genetically inherited disease, with mortality and morbidity associated with respiratory disease. The inflammatory response in CF is characterized by excessive neutrophil influx to the airways, mainly due to the increased local production and retention of interleukin-8 (IL-8), a potent neutrophil chemoattractant. AREAS COVERED We discuss how the chemokine IL-8 dominates the inflammatory profile of the airways in CF lung disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are designed to correct the malfunctioning protein resulting from specific CFTR mutations. This review covers current evidence on the impact of CFTR impairment on levels of IL-8 and outlines the influence of effective CFTR modulation on inflammation in CF with a focus on cytokine production. Review of the literature was carried out using the PUBMED database, Google Scholar, and The Cochrane Library databases, using several appropriate generic terms. EXPERT OPINION Therapeutic interventions specifically targeting the defective CFTR protein have improved the outlook for CF. Accumulating studies on the effect of highly effective CFTR modulation on inflammation indicate an impact on IL-8 levels. Further studies are required to increase our knowledge of early onset innate inflammatory dysregulation and on anti-inflammatory mechanisms of CFTR modulators.
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Affiliation(s)
- Michael Williamson
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Michelle Casey
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Claudie Gabillard-Lefort
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Aram Alharbi
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Yu Qing Jolene Teo
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Noel G McElvaney
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Emer P Reeves
- Royal College of Surgeons in Ireland, Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
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30
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Marques PE, Vandendriessche S, de Oliveira THC, Crijns H, Lopes ME, Blanter M, Schuermans S, Yu K, Poosti F, Vanheule V, Janssens R, Boff D, Kungl AJ, Menezes GB, Teixeira MM, Proost P. Inhibition of Drug-Induced Liver Injury in Mice Using a Positively Charged Peptide That Binds DNA. Hepatol Commun 2021; 5:1737-1754. [PMID: 34532999 PMCID: PMC8485890 DOI: 10.1002/hep4.1759] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 04/30/2021] [Accepted: 05/11/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatic cell death occurs in response to diverse stimuli such as chemical and physical damage. The exposure of intracellular contents such as DNA during necrosis induces a severe inflammatory response that has yet to be fully explored therapeutically. Here, we sought means to neutralize the ability of extracellular DNA to induce deleterious tissue inflammation when drug-induced liver injury had already ensued. DNA exposure and inflammation were investigated in vivo in drug-induced liver injury using intravital microscopy. The necrotic DNA debris was studied in murine livers in vivo and in DNA debris models in vitro by using a positively charged chemokine-derived peptide (MIG30; CXCL9[74-103]). Acetaminophen-induced liver necrosis was associated with massive DNA accumulation, production of CXC chemokines, and neutrophil activation inside the injured tissue. The MIG30 peptide bound the healthy liver vasculature and, to a much greater extent, to DNA-rich necrotic tissue. Moreover, MIG30 bound extracellular DNA directly in vivo in a charge-dependent manner and independently of glycosaminoglycans and chemokines. Post-treatment of mice with MIG30 reduced mortality, liver damage, and inflammation significantly. These effects were not observed with a control peptide that does not bind DNA. Mechanistically, MIG30 inhibited the interaction between DNA and histones, and promoted the dissociation of histones from necrotic debris. MIG30 also inhibited the pro-inflammatory effect of CpG DNA, as measured by a reduction in CXCL8 production, indicating that MIG30 disturbs the ability of DNA to induce hepatic inflammation. Conclusion: The use of DNA-binding peptides reduces necrotic liver injury and inflammation, even at late timepoints.
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Affiliation(s)
- Pedro E Marques
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Sofie Vandendriessche
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Thiago H C de Oliveira
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Helena Crijns
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Mateus E Lopes
- Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Marfa Blanter
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Sara Schuermans
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Karen Yu
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Fariba Poosti
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Vincent Vanheule
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Rik Janssens
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
| | - Daiane Boff
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium.,Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Andreas J Kungl
- Department of Pharmaceutical ChemistryInstitute of Pharmaceutical SciencesKarl-Franzens UniversitätGrazAustria
| | - Gustavo B Menezes
- Center for Gastrointestinal BiologyDepartment of MorphologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Mauro M Teixeira
- Immunopharmacology LaboratoryDepartment of Biochemistry and ImmunologyUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Paul Proost
- Laboratory of Molecular ImmunologyDepartment of Microbiology, Immunology and TransplantationRega Institute for Medical ResearchKU LeuvenLeuvenBelgium
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31
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Swan D, Carrier M, Lisman T, Thachil J. Heparin - Messias or Verschlimmbesserung? J Thromb Haemost 2021; 19:2373-2382. [PMID: 34272818 PMCID: PMC9906358 DOI: 10.1111/jth.15464] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/02/2021] [Accepted: 07/14/2021] [Indexed: 12/11/2022]
Abstract
A heightened risk of thrombosis noted early on with the severe acute respiratory syndrome coronavirus 2 infection led to the widespread use of heparin anticoagulation in the coronavirus disease 2019 (COVID-19) pandemic. However, reports soon started appearing in the literature where an apparent failure of heparin to prevent thrombotic events was observed in hospitalized patients with this viral infection. In this review, we explore the likely mechanisms for heparin failure with particular relevance to COVID-19. We also explore the role of anti-Xa assays and global hemostatic tests in this context. The current controversy of dosing heparin in this disease is detailed with some possible mechanistic reasons for anticoagulant failure. We hope that lessons learnt from the use of heparin in COVID-19 could assist us in the appropriate use of this anticoagulant in the future.
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Affiliation(s)
- Dawn Swan
- Department of Haematology, St James' Hospital, Dublin, Ireland
| | - Marc Carrier
- The Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jecko Thachil
- Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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32
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McMahon M, Ye S, Pedrina J, Dlugolenski D, Stambas J. Extracellular Matrix Enzymes and Immune Cell Biology. Front Mol Biosci 2021; 8:703868. [PMID: 34527702 PMCID: PMC8436118 DOI: 10.3389/fmolb.2021.703868] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022] Open
Abstract
Remodelling of the extracellular matrix (ECM) by ECM metalloproteinases is increasingly being associated with regulation of immune cell function. ECM metalloproteinases, including Matrix Metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs) and ADAMs with Thombospondin-1 motifs (ADAMTS) play a vital role in pathogen defence and have been shown to influence migration of immune cells. This review provides a current summary of the role of ECM enzymes in immune cell migration and function and discusses opportunities and limitations for development of diagnostic and therapeutic strategies targeting metalloproteinase expression and activity in the context of infectious disease.
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Affiliation(s)
- Meagan McMahon
- Faculty of Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Siying Ye
- Faculty of Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Jess Pedrina
- Faculty of Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - Daniel Dlugolenski
- Faculty of Health, School of Medicine, Deakin University, Geelong, VIC, Australia
| | - John Stambas
- Faculty of Health, School of Medicine, Deakin University, Geelong, VIC, Australia
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33
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Sadgrove NJ, Simmonds MSJ. Pharmacodynamics of Aloe vera and acemannan in therapeutic applications for skin, digestion, and immunomodulation. Phytother Res 2021; 35:6572-6584. [PMID: 34427371 DOI: 10.1002/ptr.7242] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 07/25/2021] [Accepted: 08/02/2021] [Indexed: 12/16/2022]
Abstract
Scientific studies of Aloe vera have tentatively explained therapeutic claims from a mechanistic perspective. Furthermore, in vitro outcomes demonstrate that the breakage of acemannan chains into smaller fragments enhances biological effects. These fragments can intravenously boost vaccine efficacy or entrain the immune system to attack cancer cells by mannose receptor agonism of macrophage or dendritic cells. With oral consumption, epithelialisation also occurs at injured sites in the small intestine or colon. The main advantage of dietary acemannan is the attenuation of the digestive process, increasing satiety, and slowing the release of sugars from starches. In the colon, acemannan is digested by microbes into short-chain fatty acids that are absorbed and augment the sensation of satiety and confer a host of other health benefits. In topical applications, an acemannan/chitosan combination accelerates the closure of wounds by promoting granular tissue formation, which creates a barrier between macrophages or neutrophils and the wound dressing. This causes M2 polarisation, reversal of inflammation, and acceleration of the re-epithelialisation process. This review summarises and explains the current pharmacodynamic paradigm in the context of acemannan in topical, oral, and intravenous applications. However, due to contradictory results in the literature, further research is required to provide scientific evidence to confirm or nullify these claims.
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34
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Kaul A, Short WD, Keswani SG, Wang X. Immunologic Roles of Hyaluronan in Dermal Wound Healing. Biomolecules 2021; 11:1234. [PMID: 34439900 PMCID: PMC8394879 DOI: 10.3390/biom11081234] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA's length of linearly repeating disaccharides-in other words, its molecular weight (MW)-determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA's involvement in the immune subsystems.
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Affiliation(s)
| | | | - Sundeep G. Keswani
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX 77030, USA; (A.K.); (W.D.S.)
| | - Xinyi Wang
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX 77030, USA; (A.K.); (W.D.S.)
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35
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Dickhout A, Kaczor DM, Heinzmann ACA, Brouns SLN, Heemskerk JWM, van Zandvoort MAMJ, Koenen RR. Rapid Internalization and Nuclear Translocation of CCL5 and CXCL4 in Endothelial Cells. Int J Mol Sci 2021; 22:ijms22147332. [PMID: 34298951 PMCID: PMC8305033 DOI: 10.3390/ijms22147332] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 06/27/2021] [Accepted: 07/02/2021] [Indexed: 11/16/2022] Open
Abstract
The chemokines CCL5 and CXCL4 are deposited by platelets onto endothelial cells, inducing monocyte arrest. Here, the fate of CCL5 and CXCL4 after endothelial deposition was investigated. Human umbilical vein endothelial cells (HUVECs) and EA.hy926 cells were incubated with CCL5 or CXCL4 for up to 120 min, and chemokine uptake was analyzed by microscopy and by ELISA. Intracellular calcium signaling was visualized upon chemokine treatment, and monocyte arrest was evaluated under laminar flow. Whereas CXCL4 remained partly on the cell surface, all of the CCL5 was internalized into endothelial cells. Endocytosis of CCL5 and CXCL4 was shown as a rapid and active process that primarily depended on dynamin, clathrin, and G protein-coupled receptors (GPCRs), but not on surface proteoglycans. Intracellular calcium signals were increased after chemokine treatment. Confocal microscopy and ELISA measurements in cell organelle fractions indicated that both chemokines accumulated in the nucleus. Internalization did not affect leukocyte arrest, as pretreatment of chemokines and subsequent washing did not alter monocyte adhesion to endothelial cells. Endothelial cells rapidly and actively internalize CCL5 and CXCL4 by clathrin and dynamin-dependent endocytosis, where the chemokines appear to be directed to the nucleus. These findings expand our knowledge of how chemokines attract leukocytes to sites of inflammation.
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Affiliation(s)
- Annemiek Dickhout
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
| | - Dawid M. Kaczor
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
| | - Alexandra C. A. Heinzmann
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
| | - Sanne L. N. Brouns
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
| | - Johan W. M. Heemskerk
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
| | - Marc A. M. J. van Zandvoort
- Department of Genetics and Cell Biology, Molecular Cell Biology, School for Oncology and Developmental Biology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Institute for Molecular Cardiovascular Research IMCAR, RWTH Aachen University, 52074 Aachen, Germany
| | - Rory R. Koenen
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, 6229 ER Maastricht, The Netherlands; (A.D.); (D.M.K.); (A.C.A.H.); (S.L.N.B.); (J.W.M.H.)
- Institute for Cardiovascular Prevention (IPEK), LMU Munich, 80336 Munich, Germany
- Correspondence:
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Yang Y, Lu Y, Zeng K, Heinze T, Groth T, Zhang K. Recent Progress on Cellulose-Based Ionic Compounds for Biomaterials. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2021; 33:e2000717. [PMID: 32270900 PMCID: PMC11469321 DOI: 10.1002/adma.202000717] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/25/2020] [Accepted: 02/26/2020] [Indexed: 05/06/2023]
Abstract
Glycans play important roles in all major kingdoms of organisms, such as archea, bacteria, fungi, plants, and animals. Cellulose, the most abundant polysaccharide on the Earth, plays a predominant role for mechanical stability in plants, and finds a plethora of applications by humans. Beyond traditional use, biomedical application of cellulose becomes feasible with advances of soluble cellulose derivatives with diverse functional moieties along the backbone and modified nanocellulose with versatile functional groups on the surface due to the native features of cellulose as both cellulose chains and supramolecular ordered domains as extractable nanocellulose. With the focus on ionic cellulose-based compounds involving both these groups primarily for biomedical applications, a brief introduction about glycoscience and especially native biologically active glycosaminoglycans with specific biomedical application areas on humans is given, which inspires further development of bioactive compounds from glycans. Then, both polymeric cellulose derivatives and nanocellulose-based compounds synthesized as versatile biomaterials for a large variety of biomedical applications, such as for wound dressings, controlled release, encapsulation of cells and enzymes, and tissue engineering, are separately described, regarding the diverse routes of synthesis and the established and suggested applications for these highly interesting materials.
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Affiliation(s)
- Yang Yang
- Wood Technology and Wood ChemistryUniversity of GoettingenBüsgenweg 4Göttingen37077Germany
- State Key Laboratory of Pulp and Paper EngineeringSouth China University of TechnologyWushan Road 381Guangzhou510640P. R. China
| | - Yi‐Tung Lu
- Department Biomedical MaterialsInstitute of PharmacyMartin Luther University Halle‐WittenbergHeinrich‐Damerow‐Strasse 4Halle (Saale)06120Germany
| | - Kui Zeng
- Wood Technology and Wood ChemistryUniversity of GoettingenBüsgenweg 4Göttingen37077Germany
| | - Thomas Heinze
- Institute of Organic Chemistry and Macromolecular ChemistryFriedrich Schiller University of JenaCentre of Excellence for Polysaccharide ResearchHumboldt Straße 10JenaD‐07743Germany
| | - Thomas Groth
- Department Biomedical MaterialsInstitute of PharmacyMartin Luther University Halle‐WittenbergHeinrich‐Damerow‐Strasse 4Halle (Saale)06120Germany
- Interdisciplinary Center of Materials ScienceMartin Luther University Halle‐WittenbergHalle (Saale)06120Germany
- Laboratory of Biomedical NanotechnologiesInstitute of Bionic Technologies and EngineeringI. M. Sechenov First Moscow State UniversityTrubetskaya Street 8119991MoscowRussian Federation
| | - Kai Zhang
- Wood Technology and Wood ChemistryUniversity of GoettingenBüsgenweg 4Göttingen37077Germany
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Lima LG, Ham S, Shin H, Chai EPZ, Lek ESH, Lobb RJ, Müller AF, Mathivanan S, Yeo B, Choi Y, Parker BS, Möller A. Tumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution. Nat Commun 2021; 12:3543. [PMID: 34112803 PMCID: PMC8192925 DOI: 10.1038/s41467-021-23946-8] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 05/26/2021] [Indexed: 01/17/2023] Open
Abstract
Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings. Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.
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Affiliation(s)
- Luize G Lima
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Sunyoung Ham
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.,School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Hyunku Shin
- Department of Bio-convergence Engineering, Korea University, Seoul, South Korea
| | - Edna P Z Chai
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Erica S H Lek
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.,School of Chemistry and Molecular Biosciences, Faculty of Science, University of Queensland, Brisbane, QLD, Australia
| | - Richard J Lobb
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.,Centre for Personalized Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, Brisbane, QLD, Australia
| | - Alexandra F Müller
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Suresh Mathivanan
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Belinda Yeo
- Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, Melbourne, VIC, Australia
| | - Yeonho Choi
- Department of Bio-convergence Engineering, Korea University, Seoul, South Korea.,School of Biomedical Engineering, Korea University, Seoul, South Korea.,Department of Bioengineering, Korea University, Seoul, South Korea
| | - Belinda S Parker
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Andreas Möller
- Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. .,School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. .,Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
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Pontejo SM, Murphy PM. Chemokines act as phosphatidylserine-bound "find-me" signals in apoptotic cell clearance. PLoS Biol 2021; 19:e3001259. [PMID: 34038417 PMCID: PMC8213124 DOI: 10.1371/journal.pbio.3001259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/18/2021] [Accepted: 05/05/2021] [Indexed: 12/14/2022] Open
Abstract
Removal of apoptotic cells is essential for maintenance of tissue homeostasis. Chemotactic cues termed "find-me" signals attract phagocytes toward apoptotic cells, which selectively expose the anionic phospholipid phosphatidylserine (PS) and other "eat-me" signals to distinguish healthy from apoptotic cells for phagocytosis. Blebs released by apoptotic cells can deliver find-me signals; however, the mechanism is poorly understood. Here, we demonstrate that apoptotic blebs generated in vivo from mouse thymus attract phagocytes using endogenous chemokines bound to the bleb surface. We show that chemokine binding to apoptotic cells is mediated by PS and that high affinity binding of PS and other anionic phospholipids is a general property of many but not all chemokines. Chemokines are positively charged proteins that also bind to anionic glycosaminoglycans (GAGs) on cell surfaces for presentation to leukocyte G protein-coupled receptors (GPCRs). We found that apoptotic cells down-regulate GAGs as they up-regulate PS on the cell surface and that PS-bound chemokines, unlike GAG-bound chemokines, are able to directly activate chemokine receptors. Thus, we conclude that PS-bound chemokines may serve as find-me signals on apoptotic vesicles acting at cognate chemokine receptors on leukocytes.
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Affiliation(s)
- Sergio M Pontejo
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Philip M Murphy
- Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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Perea L, Cantó E, Suarez-Cuartin G, Aliberti S, Chalmers JD, Sibila O, Vidal S. A Cluster Analysis of Bronchiectasis Patients Based on the Airway Immune Profile. Chest 2021; 159:1758-1767. [PMID: 33217421 DOI: 10.1016/j.chest.2020.11.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Clinical heterogeneity in bronchiectasis remains a challenge for improving the appropriate targeting of therapies and patient management. Antimicrobial peptides (AMPs) have been linked to disease severity and phenotype. RESEARCH QUESTION Can we identify clusters of patients based on the levels of AMPs, airway inflammation, tissue remodeling, and tissue damage to establish their relationship with disease severity and clinical outcomes? STUDY DESIGN AND METHODS A prospective cohort of 128 stable patients with bronchiectasis were recruited across three centers in three different countries (Spain, Scotland, and Italy). A two-step cluster strategy was used to stratify patients according to levels of lactoferrin, lysozyme, LL-37, and secretory leukocyte protease inhibitor in sputum. Measurements of inflammation (IL-8, tumor growth factor β, and IL-6), tissue remodeling and damage (glycosaminoglycan, matrix metallopeptidase 9, neutrophil elastase, and total and bacterial DNA), and neutrophil chemotaxis were assessed. RESULTS Three clusters of patients were defined according to distinct airway profiles of AMPs. They represented groups of patients with gradually distinct airway infection and disease severity. Each cluster was associated with an airway profile of inflammation, tissue remodeling, and tissue damage. The relationships between soluble mediators also were distinct between clusters. This analysis allowed the identification of the cluster with the most deregulated local innate immune response. During follow-up, each cluster showed different risk of three or more exacerbations occurring (P = .03) and different times to first exacerbations (P = .03). INTERPRETATION Bronchiectasis patients can be stratified in different clusters according to profiles of airway AMPs, inflammation, tissue remodeling, and tissue damage. The combination of these immunologic variables shows a relationship with disease severity and future risk of exacerbations.
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Affiliation(s)
- Lídia Perea
- Department of Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Elisabet Cantó
- Department of Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Guillermo Suarez-Cuartin
- Respiratory Department, Hospital Universitari de Bellvitge, l'Hospitalet de Llobregat, Barcelona, Spain
| | - Stefano Aliberti
- Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - James D Chalmers
- Tayside Respiratory Research Group, University of Dundee, Dundee, Scotland
| | - Oriol Sibila
- Respiratory Department, Hospital Clinic, IDIBAPS, CIBERES, University of Barcelona, Barcelona, Spain
| | - Silvia Vidal
- Department of Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
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Gerlza T, Nagele M, Mihalic Z, Trojacher C, Kungl A. Glycosaminoglycans located on neutrophils and monocytes impact on CXCL8- and CCL2-induced cell migration. Cytokine 2021; 142:155503. [PMID: 33781652 DOI: 10.1016/j.cyto.2021.155503] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/11/2021] [Accepted: 03/12/2021] [Indexed: 01/27/2023]
Abstract
The role of glycosaminoglycans on the surface of immune cells has so far been less studied compared to their participation in inflammatory responses as members of the endothelium and the extracellular matrix. In this study we have therefore investigated if glycosaminoglycans on immune cells act in concert with GPC receptors (i.e. both being cis-located on leukocytes) in chemokine-induced leukocyte mobilisation. For this purpose, freshly-prepared human neutrophils and monocytes were treated with heparinase III or chondroitinase ABC to digest heparan sulfate -chains or chondroitin sulfate-chains, respectively, from the leukocyte surfaces. Subsequent analysis of CXCL8- and CCL2-induced chemotaxis revealed that leukocyte migration was strongly reduced after eliminating heparan sulfate from the surface of neutrophils and monocytes. In the case of monocytes, an additional dependence of CCL2-induced chemotaxis on chondroitin sulfate was observed. We compared these results with the effect on chemotaxis of a heparan sulfate masking antibody and obtained similarly reduced migration. Following our findings, we postulate that glycosaminoglycans located on target leukocytes act synergistically with GPC receptors on immune cell migration, which is further influenced by glycosaminoglycans located on the inflamed tissue (i.e. trans with respect to the immune cell/GPC receptor). Both glycosaminoglycan localization sites seem to be important during inflammatory processes and could potentially be tackled in chemokine-related diseases.
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Affiliation(s)
- Tanja Gerlza
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Universitätsplatz 1, A-8010 Graz, Austria
| | - Margareta Nagele
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Universitätsplatz 1, A-8010 Graz, Austria
| | - Zala Mihalic
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Universitätsplatz 1, A-8010 Graz, Austria
| | - Christina Trojacher
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Universitätsplatz 1, A-8010 Graz, Austria
| | - Andreas Kungl
- Karl-Franzens-University Graz, Institute of Pharmaceutical Sciences, Universitätsplatz 1, A-8010 Graz, Austria; Antagonis Biotherapeutics GmbH, Strasserhofweg 77a, A-8045 Graz, Austria.
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Murphy-Schafer AR, Paust S. Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection. Front Cell Infect Microbiol 2021; 11:580679. [PMID: 33680987 PMCID: PMC7935524 DOI: 10.3389/fcimb.2021.580679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Influenza A virus (IAV) is a respiratory pathogen that infects millions of people each year. Both seasonal and pandemic strains of IAV are capable of causing severe respiratory disease with a high risk of respiratory failure and opportunistic secondary infection. A strong inflammatory cytokine response is a hallmark of severe IAV infection. The widespread tissue damage and edema in the lung during severe influenza is largely attributed to an overexuberant production of inflammatory cytokines and cell killing by resident and infiltrating leukocytes. Mast cells (MCs) are a sentinel hematopoietic cell type situated at mucosal sites, including the lung. Poised to react immediately upon detecting infection, MCs produce a vast array of immune modulating molecules, including inflammatory cytokines, chemokines, and proteases. As such, MCs have been implicated as a source of the immunopathology observed in severe influenza. However, a growing body of evidence indicates that MCs play an essential role not only in inducing an inflammatory response but in suppressing inflammation as well. MC-derived immune suppressive cytokines are essential to the resolution of a number of viral infections and other immune insults. Absence of MCs prolongs infection, exacerbates tissue damage, and contributes to dissemination of the pathogen to other tissues. Production of cytokines such as IL-10 and IL-6 by MCs is essential for mitigating the inflammation and tissue damage caused by innate and adaptive immune cells alike. The two opposing functions of MCs-one pro-inflammatory and one anti-inflammatory-distinguish MCs as master regulators of immunity at the site of infection. Amongst the first cells to respond to infection or injury, MCs persist for the duration of the infection, modulating the recruitment, activation, and eventual suppression of other immune cells. In this review, we will discuss the immune modulatory roles of MCs over the course of viral infection and propose that the immune suppressive mediators produced by MCs are vital to minimizing immunopathology during influenza infection.
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Affiliation(s)
| | - Silke Paust
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, United States
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Baba O, Huang LH, Elvington A, Szpakowska M, Sultan D, Heo GS, Zhang X, Luehmann H, Detering L, Chevigné A, Liu Y, Randolph GJ. CXCR4-Binding Positron Emission Tomography Tracers Link Monocyte Recruitment and Endothelial Injury in Murine Atherosclerosis. Arterioscler Thromb Vasc Biol 2021; 41:822-836. [PMID: 33327748 PMCID: PMC8105279 DOI: 10.1161/atvbaha.120.315053] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE vMIP-II (viral macrophage inflammatory protein 2)/vCCL2 (viral chemotactic cytokine ligand 2) binds to multiple chemokine receptors, and vMIP-II-based positron emission tomography tracer (64Cu-DOTA-vMIP-II: vMIP-II tracer) accumulates at atherosclerotic lesions in mice. Given that it would be expected to react with multiple chemokine receptors on monocytes and macrophages, we wondered if its accumulation in atherosclerosis lesion-bearing mice might correlate with overall macrophage burden or, alternatively, the pace of monocyte recruitment. Approach and Results: We employed a mouse model of atherosclerosis regression involving adenoassociated virus 8 vector encoding murine Apoe (AAV-mApoE) treatment of Apoe-/- mice where the pace of monocyte recruitment slows before macrophage burden subsequently declines. Accumulation of 64Cu-DOTA-vMIP-II at Apoe-/- plaque sites was strong but declined with AAV-mApoE-induced decline in monocyte recruitment, before macrophage burden reduced. Monocyte depletion indicated that monocytes and macrophages themselves were not the only target of the 64Cu-DOTA-vMIP-II tracer. Using fluorescence-tagged vMIP-II tracer, competitive receptor blocking with CXCR4 antagonists, endothelial-specific Cre-mediated deletion of CXCR4, CXCR4-specific tracer 64Cu-DOTA-FC131, and CXCR4 staining during disease progression and regression, we show endothelial cell expression of CXCR4 is a key target of 64Cu-DOTA-vMIP-II imaging. Expression of CXCR4 was low in nonplaque areas but strongly detected on endothelium of progressing plaques, especially on proliferating endothelium, where vascular permeability was increased and monocyte recruitment was the strongest. CONCLUSIONS Endothelial injury status of plaques is marked by CXCR4 expression and this injury correlates with the tendency of such plaques to recruit monocytes. Furthermore, our findings suggest positron emission tomography tracers that mark CXCR4 can be used translationally to monitor the state of plaque injury and monocyte recruitment.
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MESH Headings
- Animals
- Aorta, Thoracic/diagnostic imaging
- Aorta, Thoracic/immunology
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Atherosclerosis/diagnostic imaging
- Atherosclerosis/immunology
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Biomarkers/metabolism
- Cell Line
- Chemokines/administration & dosage
- Chemokines/pharmacokinetics
- Disease Models, Animal
- Endothelial Cells/immunology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelium, Vascular/diagnostic imaging
- Endothelium, Vascular/immunology
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/pathology
- Injections, Intravenous
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Knockout, ApoE
- Molecular Imaging
- Monocytes/immunology
- Monocytes/metabolism
- Monocytes/pathology
- Organometallic Compounds/administration & dosage
- Organometallic Compounds/pharmacokinetics
- Plaque, Atherosclerotic
- Positron-Emission Tomography
- Predictive Value of Tests
- Radiopharmaceuticals/administration & dosage
- Radiopharmaceuticals/pharmacokinetics
- Receptors, CXCR4/genetics
- Receptors, CXCR4/metabolism
- Mice
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Affiliation(s)
- Osamu Baba
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis
| | - Li-Hao Huang
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis
| | - Andrew Elvington
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis
| | - Martyna Szpakowska
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Deborah Sultan
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Gyu Seong Heo
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Xiaohui Zhang
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Hannah Luehmann
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Lisa Detering
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Andy Chevigné
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Yongjian Liu
- Department of Radiology, Washington University School of Medicine, St. Louis
| | - Gwendalyn J. Randolph
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis
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Yu M, Zhang T, Zhang W, Sun Q, Li H, Li JP. Elucidating the Interactions Between Heparin/Heparan Sulfate and SARS-CoV-2-Related Proteins-An Important Strategy for Developing Novel Therapeutics for the COVID-19 Pandemic. Front Mol Biosci 2021; 7:628551. [PMID: 33569392 PMCID: PMC7868326 DOI: 10.3389/fmolb.2020.628551] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
Owing to the high mortality and the spread rate, the infectious disease caused by SARS-CoV-2 has become a major threat to public health and social economy, leading to over 70 million infections and 1. 6 million deaths to date. Since there are currently no effective therapeutic or widely available vaccines, it is of urgent need to look for new strategies for the treatment of SARS-CoV-2 infection diseases. Binding of a viral protein onto cell surface heparan sulfate (HS) is generally the first step in a cascade of interaction that is required for viral entry and the initiation of infection. Meanwhile, interactions of selectins and cytokines (e.g., IL-6 and TNF-α) with HS expressed on endothelial cells are crucial in controlling the recruitment of immune cells during inflammation. Thus, structurally defined heparin/HS and their mimetics might serve as potential drugs by competing with cell surface HS for the prevention of viral adhesion and modulation of inflammatory reaction. In this review, we will elaborate coronavirus invasion mechanisms and summarize the latest advances in HS-protein interactions, especially proteins relevant to the process of coronavirus infection and subsequent inflammation. Experimental and computational techniques involved will be emphasized.
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Affiliation(s)
- Mingjia Yu
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China
| | - Tianji Zhang
- Division of Chemistry and Analytical Science, National Institute of Metrology, Beijing, China
| | - Wei Zhang
- Division of Chemistry and Analytical Science, National Institute of Metrology, Beijing, China
| | - Qianyun Sun
- Division of Chemistry, Shandong Institute of Metrology, Jinan, China
| | - Hongmei Li
- Division of Chemistry and Analytical Science, National Institute of Metrology, Beijing, China
| | - Jin-ping Li
- Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, China
- Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden
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Gangele K, Gulati K, Joshi N, Kumar D, Poluri KM. Molecular insights into the differential structure-dynamics-stability features of interleukin-8 orthologs: Implications to functional specificity. Int J Biol Macromol 2020; 164:3221-3234. [PMID: 32853623 DOI: 10.1016/j.ijbiomac.2020.08.176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/20/2020] [Accepted: 08/21/2020] [Indexed: 11/17/2022]
Abstract
Chemokines are a sub-group of chemotactic cytokines that regulate the leukocyte migration by binding to G-protein coupled receptors (GPCRs) and cell surface glycosaminoglycans (GAGs). Interleukin-8 (CXCL8/IL8) is one of the most essential CXC chemokine that has been reported to be involved in various pathophysiological conditions. Structure-function relationships of human IL8 have been studied extensively. However, no such detailed information is available on IL8 orthologs, although they exhibit significant functional divergence. In order to unravel the differential structure-dynamics-stability-function relationship of IL8 orthologs, comparative molecular analysis was performed on canine (laurasians) and human (primates) IL8 proteins using in-silico molecular evolutionary analysis and solution NMR spectroscopy methods. The residue level NMR studies suggested that, although the overall structural architecture of canine IL8 is similar to that of human IL8, systematic differences were observed in their backbone dynamics and low-energy excited states due to amino acid substitutions. Further, these substitutions also resulted in attenuation of stability and heparin binding affinity in the canine IL8 as compared to its human counterpart. Indeed, structural and sequence analysis evidenced for specificity of molecular interactions with cognate receptor (CXCR1) and glycosaminoglycan (heparin), thus providing evidence for a noticeable functional specificity and divergence between the two IL8 orthologs.
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Affiliation(s)
- Krishnakant Gangele
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
| | - Khushboo Gulati
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
| | - Nidhi Joshi
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India
| | - Dinesh Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow 226014, Uttar Pradesh, India
| | - Krishna Mohan Poluri
- Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India; Centre for Nanotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India.
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45
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Xie X, Zheng T, Li W. Recent Progress in Ionic Coassembly of Cationic Peptides and Anionic Species. Macromol Rapid Commun 2020; 41:e2000534. [PMID: 33225490 DOI: 10.1002/marc.202000534] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/10/2020] [Indexed: 12/25/2022]
Abstract
Peptide assembly has been extensively exploited as a promising platform for the creation of hierarchical nanostructures and tailor-made bioactive materials. Ionic coassembly of cationic peptides and anionic species is paving the way to provide particularly important contribution to this topic. In this review, the recent progress of ionic coassembly soft materials derived from the electrostatic coupling between cationic peptides and anionic species in aqueous solution is systematically summarized. The presentation of this review starts from a brief background on the general importance and advantages of peptide-based ionic coassembly. After that, diverse combinations of cationic peptides with small anions, macro- and/or oligo-anions, anionic polymers, and inorganic polyoxometalates are described. Emphasis is placed on the hierarchical structures, value-added properties, and applications. The molecular design of cationic peptides and the general principles behind the ionic coassembled structures are discussed. It is summarized that the combination of interesting and unique characteristics that arise both from the chemical diversity of peptides and the wide range of anionic species may contribute in a variety of output, including drug delivery, tissue engineering, gene transfection, and antibacterial activity. The emergent new phenomena and findings are illustrated. Finally, the outlook for the peptide-based ionic coassembly systems is also presented.
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Affiliation(s)
- Xiaoming Xie
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Qianjing Avenue 2699, Changchun, 130012, China.,Department of Chemistry, Xinzhou Teachers' University, Xinzhou, Shanxi, 034000, China
| | - Tingting Zheng
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Qianjing Avenue 2699, Changchun, 130012, China
| | - Wen Li
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Qianjing Avenue 2699, Changchun, 130012, China
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Abstract
♦ Background By virtue of their high net negative charge, glycosaminoglycans and proteoglycans play pivotal roles in biologic processes such as cell–cell and cell–matrix interactions, sequestration of growth factors, activation of chemokines and cytokines, and permselectivity of basement membranes. ♦ Methods The present article reviews the putative roles of glycosaminoglycans and proteoglycans in the peritoneal cavity during normal peritoneal homeostasis and chronic inflammation, the latter induced by constant exposure of the peritoneum to non-physiologic peritoneal dialysis (PD) solutions. ♦ Results Glycosaminoglycans have been identified in the mesothelial glycocalyx, a slippery, non-adhesive layer that protects the peritoneal membrane from abrasion and infection. Dermatan sulfate proteoglycans can neutralize the activity of transforming growth factor β1 and can thus play an essential role in modulating peritoneal fibrosis. Heparan sulfate proteoglycans play a crucial role in the sequestration of growth factors; they also modulate selective permeability of proteins across the peritoneal cavity. Reduced expression of perlecan, a heparan sulfate proteoglycan of the basement membrane, is observed in peritoneal biopsies obtained from established PD patients, consequent to prolonged exposure to the elevated glucose concentrations in conventional PD solutions. Supplementation of PD fluids with glycosaminoglycans has been shown to be beneficial to both the structural and functional integrity of the peritoneum. ♦ Conclusions Recent advances in the field of glycobiology have revealed a multitude of biologic processes that are controlled or influenced by glycosaminoglycans and proteoglycans. Altered synthesis of these macromolecules during PD has serious implications for the peritoneal transport of proteins, host defense, wound healing, inflammation, and fibrosis.
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Affiliation(s)
- Susan Yung
- Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
| | - Chan Tak Mao
- Department of Medicine, University of Hong Kong, Hong Kong SAR, PR China
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Clauder F, Möller S, Köhling S, Bellmann‐Sickert K, Rademann J, Schnabelrauch M, Beck‐Sickinger AG. Peptide‐mediated surface coatings for the release of wound‐healing cytokines. J Tissue Eng Regen Med 2020; 14:1738-1748. [DOI: 10.1002/term.3123] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 07/20/2020] [Accepted: 08/26/2020] [Indexed: 01/07/2023]
Affiliation(s)
- Franziska Clauder
- Institute of Biochemistry, Faculty of Life Sciences Leipzig University Leipzig Germany
| | | | - Sebastian Köhling
- Institute of Pharmacy, Medicinal Chemistry Freie Universität Berlin Berlin Germany
| | | | - Jörg Rademann
- Institute of Pharmacy, Medicinal Chemistry Freie Universität Berlin Berlin Germany
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48
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Utsunomiya T, Mimura-Kimura Y, Yamamoto T, Aoe K, Oishi K, Kamei H, Matsunaga K, Yano M, Mimura Y. Cytokine Adsorption to Polymyxin B-Immobilized Fiber: An in vitro Study. Blood Purif 2020; 50:230-237. [PMID: 32894831 DOI: 10.1159/000510290] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/17/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are episodes of acute respiratory worsening characterized by diffuse alveolar damage superimposed on usual interstitial pneumonia. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) is reported to have beneficial effects on the respiratory status and outcome in patients with AE-IPF although its mechanism of action is not fully elucidated. OBJECTIVE To investigate whether and how the PMX-immobilized fiber (PMX-F) adsorbs cytokines because reduction of the serum levels of various cytokines has been noted in AE-IPF patients receiving PMX-DHP. METHODS The propensity of recombinant cytokines for adsorption onto PMX-F was examined by incubating cytokines with heparin-coated or uncoated PMX-F for 2 h at 37°C. Cytokines were quantitated by multiplex bead array assay or ELISA. RESULTS Interleukin (IL)-8, RANTES, platelet-derived growth factor-bb, and transforming growth factor-β were substantially adsorbed onto PMX-F without heparin coating. The adsorbed cytokines could be eluted with PMX sulfate, indicating that the PMX moiety is involved in cytokine adsorption. Importantly, although IL-1β, monocyte chemoattractant protein-1, fibroblast growth factor 2, and vascular endothelial growth factor-A were adsorbed onto PMX-F to lesser extents, the adsorption was enhanced by heparin coating of PMX-F. Furthermore, heparin-coated PMX-F acquired the capability to adsorb IL-6, IL-12, and tumor necrosis factor α. An affinity of heparin to PMX was determined (Kd = 0.061 ± 0.032 mg/mL), which accounts for the enhanced cytokine adsorption onto PMX-F upon heparin coating. CONCLUSIONS Various cytokines involved in inflammation, fibrosis, and vascular permeability were shown to be adsorbed onto PMX-F. Removal of multiple cytokines may be associated with positive impacts of PMX-DHP in patients with AE-IPF.
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Affiliation(s)
- Toshiaki Utsunomiya
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan.,Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yuka Mimura-Kimura
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan
| | - Takeshi Yamamoto
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Keisuke Aoe
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan
| | - Keiji Oishi
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan
| | - Haruhito Kamei
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan
| | - Kazuto Matsunaga
- Department of Respiratory Medicine and Infectious Disease, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masafumi Yano
- Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Yusuke Mimura
- Department of Clinical Research, National Hospital Organization Yamaguchi Ube Medical Center, Ube, Japan,
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Buijsers B, Yanginlar C, Maciej-Hulme ML, de Mast Q, van der Vlag J. Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients. EBioMedicine 2020; 59:102969. [PMID: 32853989 PMCID: PMC7445140 DOI: 10.1016/j.ebiom.2020.102969] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/05/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease-2019 (COVID-19) is associated with severe inflammation in mainly the lung, and kidney. Reports suggest a beneficial effect of the use of heparin/low molecular weight heparin (LMWH) on mortality in COVID-19. In part, this beneficial effect could be explained by the anticoagulant properties of heparin/LMWH. Here, we summarise potential beneficial, non-anticoagulant mechanisms underlying treatment of COVID-19 patients with heparin/LMWH, which include: (i) Inhibition of heparanase activity, responsible for endothelial leakage; (ii) Neutralisation of chemokines, and cytokines; (iii) Interference with leukocyte trafficking; (iv) Reducing viral cellular entry, and (v) Neutralisation of extracellular cytotoxic histones. Considering the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of heparin/LMWH in COVID-19 patients. In addition, identification of specific heparin-derived sequences that are functional in targeting non-anticoagulant mechanisms may have even higher therapeutic potential for COVID-19 patients, and patients suffering from other inflammatory diseases.
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Affiliation(s)
- Baranca Buijsers
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Cansu Yanginlar
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Marissa L Maciej-Hulme
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
| | - Quirijn de Mast
- Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
| | - Johan van der Vlag
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Nijmegen, The Netherlands
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50
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Beurskens DMH, Huckriede JP, Schrijver R, Hemker HC, Reutelingsperger CP, Nicolaes GAF. The Anticoagulant and Nonanticoagulant Properties of Heparin. Thromb Haemost 2020; 120:1371-1383. [PMID: 32820487 DOI: 10.1055/s-0040-1715460] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Heparins represent one of the most frequently used pharmacotherapeutics. Discovered around 1926, routine clinical anticoagulant use of heparin was initiated only after the publication of several seminal papers in the early 1970s by the group of Kakkar. It was shown that heparin prevents venous thromboembolism and mortality from pulmonary embolism in patients after surgery. With the subsequent development of low-molecular-weight heparins and synthetic heparin derivatives, a family of related drugs was created that continues to prove its clinical value in thromboprophylaxis and in prevention of clotting in extracorporeal devices. Fundamental and applied research has revealed a complex pharmacodynamic profile of heparins that goes beyond its anticoagulant use. Recognition of the complex multifaceted beneficial effects of heparin underscores its therapeutic potential in various clinical situations. In this review we focus on the anticoagulant and nonanticoagulant activities of heparin and, where possible, discuss the underlying molecular mechanisms that explain the diversity of heparin's biological actions.
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Affiliation(s)
- Danielle M H Beurskens
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Joram P Huckriede
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Roy Schrijver
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - H Coenraad Hemker
- Synapse BV, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Chris P Reutelingsperger
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Gerry A F Nicolaes
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
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