The Experts below are selected from a list of 23232 Experts worldwide ranked by ideXlab platform
Michael J. Holtzman - One of the best experts on this subject based on the ideXlab platform.
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Chemokine complexity the case for CCL5
American Journal of Respiratory Cell and Molecular Biology, 2006Co-Authors: Mitchell H. Grayson, Michael J. HoltzmanAbstract:William of Ockham (of Ockham's Razor fame) and Albert Einstein both urged us to keep it simple, but biology, perhaps in comparison to philosophy or physics, is often a more complicated matrix. An example of the complex nature of nature is the case of Chemokine action in mediating inflammatory disease. Thus, Chemokines were associated initially with the development of inflammatory and allergic disease primarily through their role as chemoattractant cytokines. In turn, increased lung levels of the Chemokine CCL5 in patients with asthma and in mouse models of asthma (1, 2) were presumed to cause further recruitment of inflammatory cells, especially eosinophils, into airway tissue and consequent worsening of airway disease. However, this view of CCL5, and Chemokines in general, turns out to be quite naive, as underscored by an additional article in the current issue of the AJRCMB (3). In this new article, Koya and colleagues (pp 147–154) show that CCL5 selectively dampens the long-term effect of allergen challenge in mice (3). In this model, prolonged allergen exposure (out to 48 d after initial sensitization) led to airway hyperreactivity and mucous cell metaplasia, and administration of CCL5 decreased these traits, whereas treatment with anti-CCL5 antibody significantly increased them. Administration of CCL5 also caused an increase while anti-CCL5 antibody caused a decrease in BAL fluid levels of IFN-γ as well as IFN-γ-producing CD4 T cells. Moreover, anti–IFN-γ antibody treatment caused an increase in airway hyperreactivity. Together, the results suggest that CCL5 somehow stimulates the generation of IFN-γ–producing Th1 cells that protect against a prolonged allergic response. Whether concomitant changes in lung IL-12 levels are linked to this mechanism remains uncertain. Similarly, why this action takes place after longer- but not shorter-term allergen exposure still needs to be defined, but presumably relies on the delayed development of an activated Th1 cell population.
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Chemokine Signaling Regulates Apoptosis as well as Immune Cell Traffic in Host Defense
Cell cycle (Georgetown Tex.), 2006Co-Authors: Mitchell H. Grayson, Michael J. HoltzmanAbstract:In the struggle for optimal host defense against infection with viruses, two major events are critical: death of the infected host cell and proper immune cell activation at the site of infection. Here we summarize our recent work indicating that Chemokines exhibit a distinct capacity to regulate both of these events. We put particular emphasis on a recently completed study indicating that Chemokine CCL5 may prevent cell death and thereby preserve innate immune cell function in the setting of viral infection. In addition, we introduce new work to support the more traditional role of CCL5 in mediating adaptive immune cell traffic and activation in this same setting.
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Chemokine CCL5 signals required for survival during viral infection
Journal of Allergy and Clinical Immunology, 2004Co-Authors: Jeffrey W. Tyner, Osamu Uchida, Naohiro Kajiwara, Edy Y. Kim, Mary P. O'sullivan, Michael J. Walter, Donald N. Cook, Theodore M. Danoff, Michael J. HoltzmanAbstract:Abstract Rationale Inducible expression of the CCL5 (RANTES) gene is an extremely sensitive indicator of viral infection, but the functional role of CCL5 in anti-viral defense still needs to be defined. We therefore studied newly developed mice with null mutations of the CCL5 gene in a model of viral bronchiolitis/pneumonia. Methods CCL5-null and WT cells (especially T cells and macrophages) isolated from these mice were monitored after inoculation with mouse parainfluenza type I (Sendai) virus. Studies were also extended to Chemokine receptor CCR5-null mice and human cells treated with anti-CCR5 antibody and infected with respiratory syncytial virus (RSV). Results CCL5- and CCR5-null mice were immune compromised to the point of delayed viral clearance, excessive airway inflammation, and respiratory death compared to control mice. Inflammation was characterized by accumulation of virus-infected, apoptotic macrophages in the airway mucosa. Isolated CCL5- and CCR5-null macrophages (as well as human macrophages treated with anti-CCR5 antibody) were also more susceptible to virus-induced apoptosis. This susceptibility was rescued by CCL5 add-back in CCL5-null mouse macrophages and was reproduced by inhibition of G-protein/PI3K/Akt or MEK/ERK1/2 signaling in mouse and human macrophages. These same Akt and ERK pathways were resistant to endogenous activation in CCL5-null (but not wild-type) mice after viral infection in vivo. Conclusions Inducible expression of CCL5 is critical for host survival during viral infection, most likely because CCL5 protects macrophages from virus-induced apoptosis and thereby allows for effective clearance of cellular corpses that would otherwise cause excessive airway inflammation and obstruction.
Xu Wang - One of the best experts on this subject based on the ideXlab platform.
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interactions of the Chemokine CCL5 rantes with medium sized chondroitin sulfate ligands
Structure, 2015Co-Authors: Courtney Deshauer, Eathen Ryan, Tracy M. Handel, James H. Prestegard, Ashli Morgan, Xu WangAbstract:Interactions of the Chemokine CCL5 (RANTES) with glycosaminoglycans (GAGs) are crucial to the CCL5-mediated inflammation process. However, structural information on interactions between CCL5 and longer GAG fragments is lacking. In this study, the interactions between oligosaccharides derived from chondroitin sulfate and a dimeric variant of CCL5 were investigated using solution nuclear magnetic resonance. The data indicate that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop in a manner similar to interactions between Chemokine and the receptor N terminus, leading to possible stabilization of the dimer. Using 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-tagged hexasaccharides, the binding orientation of the hexasaccharides was shown to be highly dependent on the sulfation pattern of the N-acetyl galactosamine groups. Finally, a model of the CCL5 dimer complexed to chondroitin sulfate hexasaccharides was constructed using paramagnetic relaxation enhancement and intra- and intermolecular nuclear Overhauser effect constraints.
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Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands
Structure (London England : 1993), 2015Co-Authors: Courtney Deshauer, Ashli M. Morgan, Eathen Ryan, Tracy M. Handel, James H. Prestegard, Xu WangAbstract:Interactions of the Chemokine CCL5 (RANTES) with glycosaminoglycans (GAGs) are crucial to the CCL5-mediated inflammation process. However, structural information on interactions between CCL5 and longer GAG fragments is lacking. In this study, the interactions between oligosaccharides derived from chondroitin sulfate and a dimeric variant of CCL5 were investigated using solution nuclear magnetic resonance. The data indicate that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop in a manner similar to interactions between Chemokine and the receptor N terminus, leading to possible stabilization of the dimer. Using 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-tagged hexasaccharides, the binding orientation of the hexasaccharides was shown to be highly dependent on the sulfation pattern of the N-acetyl galactosamine groups. Finally, a model of the CCL5 dimer complexed to chondroitin sulfate hexasaccharides was constructed using paramagnetic relaxation enhancement and intra- and intermolecular nuclear Overhauser effect constraints.
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Oligomeric Structure of the Chemokine CCL5/RANTES from NMR, MS, and SAXS Data.
Structure (London England : 1993), 2011Co-Authors: Xu Wang, Tracy M. Handel, Caroline M. Watson, Joshua S. Sharp, James H. PrestegardAbstract:Summary CCL5 (RANTES) is a proinflammatory Chemokine known to activate leukocytes through its receptor, CCR5. Although the monomeric form of CCL5 is sufficient to cause cell migration in vitro, CCL5's propensity for aggregation is essential for migration in vivo, T cell activation and apoptosis, and HIV entry into cells. However, there is currently no structural information on CCL5 oligomers larger than the canonical CC Chemokine dimer. In this study the solution structure of a CCL5 oligomer was investigated using an integrated approach, including NMR residual dipolar couplings to determine allowed relative orientations of the component monomers, SAXS to restrict overall shape, and hydroxyl radical footprinting and NMR cross-saturation experiments to identify interface residues. The resulting model of the CCL5 oligomer provides a basis for explaining the disaggregating effect of E66 and E26 mutations and suggests mechanisms by which glycosaminoglycan binding may promote oligomer formation and facilitate cell migration in vivo.
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oligomeric structure of the Chemokine CCL5 rantes from nmr ms and saxs data
Structure, 2011Co-Authors: Xu Wang, Tracy M. Handel, Caroline M. Watson, Joshua S. Sharp, James H. PrestegardAbstract:Summary CCL5 (RANTES) is a proinflammatory Chemokine known to activate leukocytes through its receptor, CCR5. Although the monomeric form of CCL5 is sufficient to cause cell migration in vitro, CCL5's propensity for aggregation is essential for migration in vivo, T cell activation and apoptosis, and HIV entry into cells. However, there is currently no structural information on CCL5 oligomers larger than the canonical CC Chemokine dimer. In this study the solution structure of a CCL5 oligomer was investigated using an integrated approach, including NMR residual dipolar couplings to determine allowed relative orientations of the component monomers, SAXS to restrict overall shape, and hydroxyl radical footprinting and NMR cross-saturation experiments to identify interface residues. The resulting model of the CCL5 oligomer provides a basis for explaining the disaggregating effect of E66 and E26 mutations and suggests mechanisms by which glycosaminoglycan binding may promote oligomer formation and facilitate cell migration in vivo.
James H. Prestegard - One of the best experts on this subject based on the ideXlab platform.
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interactions of the Chemokine CCL5 rantes with medium sized chondroitin sulfate ligands
Structure, 2015Co-Authors: Courtney Deshauer, Eathen Ryan, Tracy M. Handel, James H. Prestegard, Ashli Morgan, Xu WangAbstract:Interactions of the Chemokine CCL5 (RANTES) with glycosaminoglycans (GAGs) are crucial to the CCL5-mediated inflammation process. However, structural information on interactions between CCL5 and longer GAG fragments is lacking. In this study, the interactions between oligosaccharides derived from chondroitin sulfate and a dimeric variant of CCL5 were investigated using solution nuclear magnetic resonance. The data indicate that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop in a manner similar to interactions between Chemokine and the receptor N terminus, leading to possible stabilization of the dimer. Using 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-tagged hexasaccharides, the binding orientation of the hexasaccharides was shown to be highly dependent on the sulfation pattern of the N-acetyl galactosamine groups. Finally, a model of the CCL5 dimer complexed to chondroitin sulfate hexasaccharides was constructed using paramagnetic relaxation enhancement and intra- and intermolecular nuclear Overhauser effect constraints.
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Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands
Structure (London England : 1993), 2015Co-Authors: Courtney Deshauer, Ashli M. Morgan, Eathen Ryan, Tracy M. Handel, James H. Prestegard, Xu WangAbstract:Interactions of the Chemokine CCL5 (RANTES) with glycosaminoglycans (GAGs) are crucial to the CCL5-mediated inflammation process. However, structural information on interactions between CCL5 and longer GAG fragments is lacking. In this study, the interactions between oligosaccharides derived from chondroitin sulfate and a dimeric variant of CCL5 were investigated using solution nuclear magnetic resonance. The data indicate that, in addition to the BBXB motif in the 40s loop, GAGs also contact residues in the N loop in a manner similar to interactions between Chemokine and the receptor N terminus, leading to possible stabilization of the dimer. Using 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl-tagged hexasaccharides, the binding orientation of the hexasaccharides was shown to be highly dependent on the sulfation pattern of the N-acetyl galactosamine groups. Finally, a model of the CCL5 dimer complexed to chondroitin sulfate hexasaccharides was constructed using paramagnetic relaxation enhancement and intra- and intermolecular nuclear Overhauser effect constraints.
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Oligomeric Structure of the Chemokine CCL5/RANTES from NMR, MS, and SAXS Data.
Structure (London England : 1993), 2011Co-Authors: Xu Wang, Tracy M. Handel, Caroline M. Watson, Joshua S. Sharp, James H. PrestegardAbstract:Summary CCL5 (RANTES) is a proinflammatory Chemokine known to activate leukocytes through its receptor, CCR5. Although the monomeric form of CCL5 is sufficient to cause cell migration in vitro, CCL5's propensity for aggregation is essential for migration in vivo, T cell activation and apoptosis, and HIV entry into cells. However, there is currently no structural information on CCL5 oligomers larger than the canonical CC Chemokine dimer. In this study the solution structure of a CCL5 oligomer was investigated using an integrated approach, including NMR residual dipolar couplings to determine allowed relative orientations of the component monomers, SAXS to restrict overall shape, and hydroxyl radical footprinting and NMR cross-saturation experiments to identify interface residues. The resulting model of the CCL5 oligomer provides a basis for explaining the disaggregating effect of E66 and E26 mutations and suggests mechanisms by which glycosaminoglycan binding may promote oligomer formation and facilitate cell migration in vivo.
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oligomeric structure of the Chemokine CCL5 rantes from nmr ms and saxs data
Structure, 2011Co-Authors: Xu Wang, Tracy M. Handel, Caroline M. Watson, Joshua S. Sharp, James H. PrestegardAbstract:Summary CCL5 (RANTES) is a proinflammatory Chemokine known to activate leukocytes through its receptor, CCR5. Although the monomeric form of CCL5 is sufficient to cause cell migration in vitro, CCL5's propensity for aggregation is essential for migration in vivo, T cell activation and apoptosis, and HIV entry into cells. However, there is currently no structural information on CCL5 oligomers larger than the canonical CC Chemokine dimer. In this study the solution structure of a CCL5 oligomer was investigated using an integrated approach, including NMR residual dipolar couplings to determine allowed relative orientations of the component monomers, SAXS to restrict overall shape, and hydroxyl radical footprinting and NMR cross-saturation experiments to identify interface residues. The resulting model of the CCL5 oligomer provides a basis for explaining the disaggregating effect of E66 and E26 mutations and suggests mechanisms by which glycosaminoglycan binding may promote oligomer formation and facilitate cell migration in vivo.
Vincent Braunersreuther - One of the best experts on this subject based on the ideXlab platform.
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CC Chemokine CCL5 plays a central role impacting infarct size and post-infarction heart failure in mice
European heart journal, 2011Co-Authors: Fabrizio Montecucco, Vincent Braunersreuther, Graziano Pelli, Sébastien Lenglet, Bénédicte M. A. Delattre, Vanessa Buatois, Florence Guilhot, Katia Galan, Nicolas Vuilleumier, Walter FerlinAbstract:Aims The Chemokine CCL5 plays a critical role as neutrophil and macrophage activator do in atherosclerosis and myocardial infarction. Thus, we investigated whether the treatment with a neutralizing monoclonal antibody (mAb) to mouse CCL5 would provide therapeutic benefit when provoking a coronary-associated ischaemic event. Methods and Results C57Bl/6 mice were submitted to left coronary artery permanent ligature. Then, various parameters were monitored for up to 21 days. At5 min and 3days after coronary occlusion, mice received one intravenous injection of the rat anti-mouse CCL5 mAb or isotype IgG control. Infarct size was assessed histologically and by measuring serum cardiac troponin I levels. Kinetics of CCL5 tissue expression, leucocyte infiltration, matrix metalloproteinase (MMP) levels, and collagen deposition were histologically assessed. Serum Chemokine levels were measured by enzyme-linked immunosorbent assay. Cardiac function and dimensions were assessed by magnetic resonance imaging (MRI). Chronic ischaemia increased both circulating and intracardiac levels of CCL5. At 24 h, treatment with the anti-CCL5 mAb resulted in a smaller infarct size and reduced circulating levels of Chemokines. This effect was associated with reduction of neutrophil and macrophage infiltration within the infarcted myocardium. After 3 days of chronic ischaemia, anti-CCL5 mAb treatment reduced cardiac MMP-9. At 7 days, collagen content was significantly lower. At 21 days, neutralizing CCL5 improved mouse survival, cardiac myocyte size, and cardiac function. Conclusion Treatment with anti-CCL5 mAb significantly reduced both infarct size and post-infarction heart failure in a mouse model of chronic cardiac ischaemia. Cardioprotective effects were associated with the reduction of leucocyte recruitment within infarcted hearts.
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Chemokine CCL5 rantes inhibition reduces myocardial reperfusion injury in atherosclerotic mice
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Vincent Braunersreuther, Amanda E. I. Proudfoot, Corinne Pellieux, Graziano Pelli, Fabienne Burger, Sabine Steffens, Christophe Montessuit, Christian Weber, Francois Mach, Claire ArnaudAbstract:Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites. The aim of the present study was to investigate the effect of Chemokine CCL5/RANTES antagonism in an in vivo mouse model of ischemia and reperfusion. ApoE(-/-) mice were submitted to 30 min ischemia, by ligature of the left coronary artery, followed by 24 h reperfusion. Intraperitoneal injection of 10 mug of CCL5/RANTES antagonist [(44)AANA(47)]-RANTES, 5 min prior to reperfusion, reduced infarct size as well as Troponin I serum levels compared to PBS-treated mice. This beneficial effect of [(44)AANA(47)]-RANTES treatment was associated with reduced leukocyte infiltration into the reperfused myocardium, as well as decreased Chemokines Ccl2/Mcp-1 and Ccl3/Mip-1alpha expression, oxidative stress, and apoptosis. However, mice deficient for the CCL5/RANTES receptor Ccr5 did not exhibit myocardium salvage in our model of ischemia-reperfusion. Furthermore, [(44)AANA(47)]-RANTES did not mediate cardioprotection in these ApoE(-/-) Ccr5(-/-) deficient mice, probably due to enhanced expression of compensatory Chemokines. This study provides the first evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial reperfusion, through its anti-inflammatory properties. Our findings indicate that blocking Chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce reperfusion injuries in patients during acute coronary syndromes.
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Involvement of the Chemokine CCL5/RANTES and its receptors in atherosclerosis and myocardial ischemia-reperfusion injury
2010Co-Authors: Vincent BraunersreutherAbstract:Cardiovascular disease is the leading cause of morbidity and mortality in the adult population in industrialized countries. It is now well-established that immuno-inflammatory processes are involved in several cardiovascular diseases, such as atherosclerosis and myocardial infarction. Chemokines are known to trigger and direct leukocyte trafficking from the blood to inflamed tissues through the binding to their cell-surface receptors. Chemokines and there receptors are involved in multiple inflammatory diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis or chronic obstructive pulmonary disease, as well as HIV infectious disease, making them particularly attractive therapeutic targets. In this thesis, we investigated the role of the Chemokine CCL5/RANTES and its receptors in atherogenesis and myocardial reperfusion injury. Using both pharmacological and genetic approaches, we showed that inhibition of CCL5/RANTES and its receptor CCR5 could represent an attractive therapeutic strategy to decrease atherosclerosis progression and limit damages due to the reperfusion of ischemic myocardium, in mice.
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involvement of the Chemokine CCL5 rantes and its receptors in atherosclerosis and myocardial ischemia reperfusion injury
2010Co-Authors: Vincent BraunersreutherAbstract:Cardiovascular disease is the leading cause of morbidity and mortality in the adult population in industrialized countries. It is now well-established that immuno-inflammatory processes are involved in several cardiovascular diseases, such as atherosclerosis and myocardial infarction. Chemokines are known to trigger and direct leukocyte trafficking from the blood to inflamed tissues through the binding to their cell-surface receptors. Chemokines and there receptors are involved in multiple inflammatory diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis or chronic obstructive pulmonary disease, as well as HIV infectious disease, making them particularly attractive therapeutic targets. In this thesis, we investigated the role of the Chemokine CCL5/RANTES and its receptors in atherogenesis and myocardial reperfusion injury. Using both pharmacological and genetic approaches, we showed that inhibition of CCL5/RANTES and its receptor CCR5 could represent an attractive therapeutic strategy to decrease atherosclerosis progression and limit damages due to the reperfusion of ischemic myocardium, in mice.
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Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice
Journal of molecular and cellular cardiology, 2009Co-Authors: Vincent Braunersreuther, Amanda E. I. Proudfoot, Corinne Pellieux, Graziano Pelli, Fabienne Burger, Sabine Steffens, Christophe Montessuit, Christian Weber, Francois Mach, Claire ArnaudAbstract:Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites. The aim of the present study was to investigate the effect of Chemokine CCL5/RANTES antagonism in an in vivo mouse model of ischemia and reperfusion. ApoE(-/-) mice were submitted to 30 min ischemia, by ligature of the left coronary artery, followed by 24 h reperfusion. Intraperitoneal injection of 10 mug of CCL5/RANTES antagonist [(44)AANA(47)]-RANTES, 5 min prior to reperfusion, reduced infarct size as well as Troponin I serum levels compared to PBS-treated mice. This beneficial effect of [(44)AANA(47)]-RANTES treatment was associated with reduced leukocyte infiltration into the reperfused myocardium, as well as decreased Chemokines Ccl2/Mcp-1 and Ccl3/Mip-1alpha expression, oxidative stress, and apoptosis. However, mice deficient for the CCL5/RANTES receptor Ccr5 did not exhibit myocardium salvage in our model of ischemia-reperfusion. Furthermore, [(44)AANA(47)]-RANTES did not mediate cardioprotection in these ApoE(-/-) Ccr5(-/-) deficient mice, probably due to enhanced expression of compensatory Chemokines. This study provides the first evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial reperfusion, through its anti-inflammatory properties. Our findings indicate that blocking Chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce reperfusion injuries in patients during acute coronary syndromes.
Amanda E. I. Proudfoot - One of the best experts on this subject based on the ideXlab platform.
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The Interaction of Heparin Tetrasaccharides with Chemokine CCL5 Is Modulated by Sulfation Pattern and pH
The Journal of biological chemistry, 2015Co-Authors: Arunima Singh, Amanda E. I. Proudfoot, Warren C. Kett, India C. Severin, Isaac Agyekum, Jiana Duan, I. Jonathan Amster, Deirdre R. Coombe, Robert J. WoodsAbstract:Abstract Interactions between Chemokines such as CCL5 and glycosaminoglycans (GAGs) are essential for creating haptotactic gradients to guide the migration of leukocytes into inflammatory sites, and the GAGs that interact with CCL5 with the highest affinity are heparan sulfates/heparin. The interaction between CCL5 and its receptor on monocytes, CCR1, is mediated through residues Arg-17 and -47 in CCL5, which overlap with the GAG-binding 44RKNR47 “BBXB” motifs. Here we report that heparin and tetrasaccharide fragments of heparin are able to inhibit CCL5-CCR1 binding, with IC50 values showing strong dependence on the pattern and extent of sulfation. Modeling of the CCL5-tetrasaccharide complexes suggested that interactions between specific sulfate and carboxylate groups of heparin and residues Arg-17 and -47 of the protein are essential for strong inhibition; tetrasaccharides lacking the specific sulfation pattern were found to preferentially bind CCL5 in positions less favorable for inhibition of the interaction with CCR1. Simulations of a 12-mer heparin fragment bound to CCL5 indicated that the oligosaccharide preferred to interact simultaneously with both 44RKNR47 motifs in the CCL5 homodimer and engaged residues Arg-47 and -17 from both chains. Direct engagement of these residues by the longer heparin oligosaccharide provides a rationalization for its effectiveness as an inhibitor of CCL5-CCR1 interaction. In this mode, histidine (His-23) may contribute to CCL5-GAG interactions when the pH drops just below neutral, as occurs during inflammation. Additionally, an examination of the contribution of pH to modulating CCL5-heparin interactions suggested a need for careful interpretation of experimental results when experiments are performed under non-physiological conditions.
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interference with oligomerization and glycosaminoglycan binding of the Chemokine CCL5 improves experimental liver injury
PLOS ONE, 2012Co-Authors: A Nellen, Amanda E. I. Proudfoot, D Heinrichs, M L Berres, Hacer Sahin, P Schmitz, C Trautwein, H E WasmuthAbstract:Background The Chemokine CCL5 is involved in the recruitment of immune cells and a subsequent activation of hepatic stellate cells (HSC) after liver injury. We here investigate whether inhibition of CCL5 oligomerization and glycosaminoglycan binding by a mutated CCL5 protein (44AANA47-CCL5) has the potential to ameliorate liver cell injury and fibrosis in vivo.
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Chemokine CCL5 rantes inhibition reduces myocardial reperfusion injury in atherosclerotic mice
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Vincent Braunersreuther, Amanda E. I. Proudfoot, Corinne Pellieux, Graziano Pelli, Fabienne Burger, Sabine Steffens, Christophe Montessuit, Christian Weber, Francois Mach, Claire ArnaudAbstract:Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites. The aim of the present study was to investigate the effect of Chemokine CCL5/RANTES antagonism in an in vivo mouse model of ischemia and reperfusion. ApoE(-/-) mice were submitted to 30 min ischemia, by ligature of the left coronary artery, followed by 24 h reperfusion. Intraperitoneal injection of 10 mug of CCL5/RANTES antagonist [(44)AANA(47)]-RANTES, 5 min prior to reperfusion, reduced infarct size as well as Troponin I serum levels compared to PBS-treated mice. This beneficial effect of [(44)AANA(47)]-RANTES treatment was associated with reduced leukocyte infiltration into the reperfused myocardium, as well as decreased Chemokines Ccl2/Mcp-1 and Ccl3/Mip-1alpha expression, oxidative stress, and apoptosis. However, mice deficient for the CCL5/RANTES receptor Ccr5 did not exhibit myocardium salvage in our model of ischemia-reperfusion. Furthermore, [(44)AANA(47)]-RANTES did not mediate cardioprotection in these ApoE(-/-) Ccr5(-/-) deficient mice, probably due to enhanced expression of compensatory Chemokines. This study provides the first evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial reperfusion, through its anti-inflammatory properties. Our findings indicate that blocking Chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce reperfusion injuries in patients during acute coronary syndromes.
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Chemokine CCL5/RANTES inhibition reduces myocardial reperfusion injury in atherosclerotic mice
Journal of molecular and cellular cardiology, 2009Co-Authors: Vincent Braunersreuther, Amanda E. I. Proudfoot, Corinne Pellieux, Graziano Pelli, Fabienne Burger, Sabine Steffens, Christophe Montessuit, Christian Weber, Francois Mach, Claire ArnaudAbstract:Although beneficial for cardiomyocyte salvage and to limit myocardial damage and cardiac dysfunction, restoration of blood flow after prolonged ischemia exacerbates myocardial injuries. Several deleterious processes that contribute to cardiomyocyte death have been proposed, including massive release of reactive oxygen species, calcium overload and hypercontracture development or leukocyte infiltration within the damaged myocardium. Chemokines are known to enhance leukocyte diapedesis at inflammatory sites. The aim of the present study was to investigate the effect of Chemokine CCL5/RANTES antagonism in an in vivo mouse model of ischemia and reperfusion. ApoE(-/-) mice were submitted to 30 min ischemia, by ligature of the left coronary artery, followed by 24 h reperfusion. Intraperitoneal injection of 10 mug of CCL5/RANTES antagonist [(44)AANA(47)]-RANTES, 5 min prior to reperfusion, reduced infarct size as well as Troponin I serum levels compared to PBS-treated mice. This beneficial effect of [(44)AANA(47)]-RANTES treatment was associated with reduced leukocyte infiltration into the reperfused myocardium, as well as decreased Chemokines Ccl2/Mcp-1 and Ccl3/Mip-1alpha expression, oxidative stress, and apoptosis. However, mice deficient for the CCL5/RANTES receptor Ccr5 did not exhibit myocardium salvage in our model of ischemia-reperfusion. Furthermore, [(44)AANA(47)]-RANTES did not mediate cardioprotection in these ApoE(-/-) Ccr5(-/-) deficient mice, probably due to enhanced expression of compensatory Chemokines. This study provides the first evidence that inhibition of CCL5/RANTES exerts cardioprotective effects during early myocardial reperfusion, through its anti-inflammatory properties. Our findings indicate that blocking Chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce reperfusion injuries in patients during acute coronary syndromes.