CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions
Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine–glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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Frontiers Media S.A.
2017-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00530/full |
| _version_ | 1811229550002044928 |
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| author | Vincent Vanheule Daiane Boff Daiane Boff Anneleen Mortier Rik Janssens Björn Petri Elzbieta Kolaczkowska Elzbieta Kolaczkowska Paul Kubes Nele Berghmans Sofie Struyf Andreas J. Kungl Mauro Martins Teixeira Flavio Almeida Amaral Paul Proost |
| author_facet | Vincent Vanheule Daiane Boff Daiane Boff Anneleen Mortier Rik Janssens Björn Petri Elzbieta Kolaczkowska Elzbieta Kolaczkowska Paul Kubes Nele Berghmans Sofie Struyf Andreas J. Kungl Mauro Martins Teixeira Flavio Almeida Amaral Paul Proost |
| author_sort | Vincent Vanheule |
| collection | DOAJ |
| description | Several acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine–glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo. Therefore, the GAG–chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103) binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU) crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93). Compared to CXCL9(74-103), CXCL9(74-93) showed equally high affinity for heparin and heparan sulfate (HS), but lower affinity for binding to chondroitin sulfate (CS) and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not by CXCL9(86-103). In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93). This could be explained by (1) the lower affinity of CXCL9(74-93) for CS, the most abundant GAG in joints, and (2) by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9(74-103) coats the vessel wall in vivo and that CXCL9(74-103) inhibits CXCL8-induced adhesion of neutrophils to the vessel wall in the murine cremaster muscle model. Thus, both affinity and specificity of chemokines and the peptides for different GAGs and the presence of specific GAGs in different tissues will determine whether competition can occur. In summary, both CXCL9 peptides inhibited neutrophil migration in vivo through interference with GAG interactions in several animal models. Shortening CXCL9(74-103) from the COOH-terminus limited its GAG-binding spectrum. |
| first_indexed | 2024-04-12T10:17:13Z |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T10:17:13Z |
| publishDate | 2017-05-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-b6d0e650048e406a9527acbea5d84f102022-12-22T03:37:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-05-01810.3389/fimmu.2017.00530266785CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan InteractionsVincent Vanheule0Daiane Boff1Daiane Boff2Anneleen Mortier3Rik Janssens4Björn Petri5Elzbieta Kolaczkowska6Elzbieta Kolaczkowska7Paul Kubes8Nele Berghmans9Sofie Struyf10Andreas J. Kungl11Mauro Martins Teixeira12Flavio Almeida Amaral13Paul Proost14Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumDepartamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumMouse Phenomics Resource Laboratory, Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaDepartment of Evolutionary Immunology, Institute of Zoology, Jagiellonian University, Krakow, PolandLaboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumImmunology Research Group, Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, CanadaLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumDepartment of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzens Universität, Graz, AustriaDepartamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, BrazilDepartamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, BelgiumSeveral acute and chronic inflammatory diseases are driven by accumulation of activated leukocytes due to enhanced chemokine expression. In addition to specific G protein-coupled receptor-dependent signaling, chemokine–glycosaminoglycan (GAG) interactions are important for chemokine activity in vivo. Therefore, the GAG–chemokine interaction has been explored as target for inhibition of chemokine activity. It was demonstrated that CXCL9(74-103) binds with high affinity to GAGs, competed with active chemokines for GAG binding and thereby inhibited CXCL8- and monosodium urate (MSU) crystal-induced neutrophil migration to joints. To evaluate the affinity and specificity of the COOH-terminal part of CXCL9 toward different GAGs in detail, we chemically synthesized several COOH-terminal CXCL9 peptides including the shorter CXCL9(74-93). Compared to CXCL9(74-103), CXCL9(74-93) showed equally high affinity for heparin and heparan sulfate (HS), but lower affinity for binding to chondroitin sulfate (CS) and cellular GAGs. Correspondingly, both peptides competed with equal efficiency for CXCL8 binding to heparin and HS but not to cellular GAGs. In addition, differences in anti-inflammatory activity between both peptides were detected in vivo. CXCL8-induced neutrophil migration to the peritoneal cavity and to the knee joint were inhibited with similar potency by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not by CXCL9(86-103). In contrast, neutrophil extravasation in the MSU crystal-induced gout model, in which multiple chemoattractants are induced, was not affected by CXCL9(74-93). This could be explained by (1) the lower affinity of CXCL9(74-93) for CS, the most abundant GAG in joints, and (2) by reduced competition with GAG binding of CXCL1, the most abundant ELR+ CXC chemokine in this gout model. Mechanistically we showed by intravital microscopy that fluorescent CXCL9(74-103) coats the vessel wall in vivo and that CXCL9(74-103) inhibits CXCL8-induced adhesion of neutrophils to the vessel wall in the murine cremaster muscle model. Thus, both affinity and specificity of chemokines and the peptides for different GAGs and the presence of specific GAGs in different tissues will determine whether competition can occur. In summary, both CXCL9 peptides inhibited neutrophil migration in vivo through interference with GAG interactions in several animal models. Shortening CXCL9(74-103) from the COOH-terminus limited its GAG-binding spectrum.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00530/fullchemokineCXCL9glycosaminoglycanneutrophilanti-inflammatorygout |
| spellingShingle | Vincent Vanheule Daiane Boff Daiane Boff Anneleen Mortier Rik Janssens Björn Petri Elzbieta Kolaczkowska Elzbieta Kolaczkowska Paul Kubes Nele Berghmans Sofie Struyf Andreas J. Kungl Mauro Martins Teixeira Flavio Almeida Amaral Paul Proost CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions Frontiers in Immunology chemokine CXCL9 glycosaminoglycan neutrophil anti-inflammatory gout |
| title | CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions |
| title_full | CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions |
| title_fullStr | CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions |
| title_full_unstemmed | CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions |
| title_short | CXCL9-Derived Peptides Differentially Inhibit Neutrophil Migration In Vivo through Interference with Glycosaminoglycan Interactions |
| title_sort | cxcl9 derived peptides differentially inhibit neutrophil migration in vivo through interference with glycosaminoglycan interactions |
| topic | chemokine CXCL9 glycosaminoglycan neutrophil anti-inflammatory gout |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00530/full |
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