The Experts below are selected from a list of 59682 Experts worldwide ranked by ideXlab platform
Daiane Boff - One of the best experts on this subject based on the ideXlab platform.
-
the chemokine fragment cxcl9 74 103 diminishes neutrophil recruitment and joint inflammation in antigen induced arthritis
Journal of Leukocyte Biology, 2018Co-Authors: Flávio A. Amaral, Vincent Vanheule, Rik Janssens, Daiane Boff, Helena Crijns, Gustavo B Menezes, Soraia Macari, Tarcilia Aparecida Silva, Paul ProostAbstract:This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.
-
cxcl9 derived peptides differentially inhibit neutrophil migration in vivo through interference with glycosaminoglycan interactions
Frontiers in Immunology, 2017Co-Authors: Vincent Vanheule, Rik Janssens, Daiane Boff, Anneleen Mortier, Bjorn Petri, Elzbieta Kolaczkowska, Paul Kubes, Nele BerghmansAbstract: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 (GPCR)-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 towards 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 by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not CXCL9(86-103), with similar potency. 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.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:Abstract The ELR-CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAG) and compete with functional intact chemokines for GAG binding, the longest peptide, i.e. CXCL9(74-103), being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by i.v. injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides: by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG-interactions.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:The ELR−CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74–103)) being the most potent. The COOH-terminal peptide CXCL9(74–103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74–103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74–103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74–103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions.
Vincent Vanheule - One of the best experts on this subject based on the ideXlab platform.
-
the chemokine fragment cxcl9 74 103 diminishes neutrophil recruitment and joint inflammation in antigen induced arthritis
Journal of Leukocyte Biology, 2018Co-Authors: Flávio A. Amaral, Vincent Vanheule, Rik Janssens, Daiane Boff, Helena Crijns, Gustavo B Menezes, Soraia Macari, Tarcilia Aparecida Silva, Paul ProostAbstract:This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.
-
cxcl9 derived peptides differentially inhibit neutrophil migration in vivo through interference with glycosaminoglycan interactions
Frontiers in Immunology, 2017Co-Authors: Vincent Vanheule, Rik Janssens, Daiane Boff, Anneleen Mortier, Bjorn Petri, Elzbieta Kolaczkowska, Paul Kubes, Nele BerghmansAbstract: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 (GPCR)-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 towards 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 by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not CXCL9(86-103), with similar potency. 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.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:Abstract The ELR-CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAG) and compete with functional intact chemokines for GAG binding, the longest peptide, i.e. CXCL9(74-103), being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by i.v. injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides: by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG-interactions.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:The ELR−CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74–103)) being the most potent. The COOH-terminal peptide CXCL9(74–103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74–103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74–103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74–103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions.
Flávio A. Amaral - One of the best experts on this subject based on the ideXlab platform.
-
the chemokine fragment cxcl9 74 103 diminishes neutrophil recruitment and joint inflammation in antigen induced arthritis
Journal of Leukocyte Biology, 2018Co-Authors: Flávio A. Amaral, Vincent Vanheule, Rik Janssens, Daiane Boff, Helena Crijns, Gustavo B Menezes, Soraia Macari, Tarcilia Aparecida Silva, Paul ProostAbstract:This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:Abstract The ELR-CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAG) and compete with functional intact chemokines for GAG binding, the longest peptide, i.e. CXCL9(74-103), being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by i.v. injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides: by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG-interactions.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:The ELR−CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74–103)) being the most potent. The COOH-terminal peptide CXCL9(74–103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74–103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74–103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74–103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions.
-
the cxcl8 il 8 chemokine family and its receptors in inflammatory diseases
Expert Review of Clinical Immunology, 2014Co-Authors: Remo Castro Russo, Mauro M Teixeira, Cristiana C Garcia, Flávio A. AmaralAbstract:Chemokines are small proteins that control several tissue functions, including cell recruitment and activation under homeostatic and inflammatory conditions. CXCL8 (interleukin-8) is a member of the chemokine family that acts on CXCR1 and CXCR2 receptors. CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, and CXCL7 are also ELR+ chemokine members that bind to these receptors, especially CXCR2. The majority of studies on the biology of CXCL8 and their receptors have been performed in polymorphonuclear leukocytes. However, many other cells express CXCR1/CXCR2, including epithelial, endothelial, fibroblasts and neurons, contributing to the biological effects of CXCL8. There is substantial amount of experimental data suggesting that CXCL8 and receptors contribute to elimination of pathogens, but may also contribute significantly to disease-associated processes, including tissue injury, fibrosis, angiogenesis and tumorigenesis. Here, we discuss the biology of CXCL8 family and the potential therapeutic use of antagonists or blockers of these molecules in the context of organ-specific diseases.
Rik Janssens - One of the best experts on this subject based on the ideXlab platform.
-
the chemokine fragment cxcl9 74 103 diminishes neutrophil recruitment and joint inflammation in antigen induced arthritis
Journal of Leukocyte Biology, 2018Co-Authors: Flávio A. Amaral, Vincent Vanheule, Rik Janssens, Daiane Boff, Helena Crijns, Gustavo B Menezes, Soraia Macari, Tarcilia Aparecida Silva, Paul ProostAbstract:This study investigates if treatment with a peptide corresponding to the 30 C-terminal amino acids of CXCL9, CXCL9(74-103), ameliorates joint inflammation in a murine model of antigen-induced arthritis (AIA). AIA was induced in male C57BL/6J mice. Intravenous injection of CXCL9(74-103), simultaneously performed with a tibiofemoral challenge with methylated BSA (mBSA) as antigen in mice immunized with mBSA, diminished the accumulation of leukocytes, in particular neutrophils, in the synovial cavity. The levels of the chemokines CXCL1, CXCL2, and CXCL6 and of the cytokine IL-6 were decreased in inflamed periarticular tissue of mice treated with the CXCL9-derived peptide compared to non-treated AIA mice. In addition, CXCL9(74-103) treatment substantially reduced joint and cartilage damage. CXCL9(74-103) competes with CXCL6 and CCL3 for binding to the glycosaminoglycans heparan sulfate and chondroitin sulfate in vitro. In vivo, CXCL9(74-103) quickly binds to blood vessels in joints as observed by confocal microscopy. Next, we evaluated if later treatment with CXCL9(74-103) had a beneficial impact on joint inflammation. CXCL9(74-103) injection 6 h after mBSA challenge still reduced neutrophil accumulation in the joint, although it did not reduce chemokine and IL-6 concentrations. However, a delay of treatment until 12 h after challenge had no effect on cell recruitment and chemokine and IL-6 levels. Taken together, we demonstrated that treatment with a peptide, which interferes with the interaction between chemokines and glycosaminoglycans, from the beginning of the disease controlled the massive accumulation of neutrophils in the joint of AIA mice, greatly impacting on joint inflammation and tissue damage.
-
cxcl9 derived peptides differentially inhibit neutrophil migration in vivo through interference with glycosaminoglycan interactions
Frontiers in Immunology, 2017Co-Authors: Vincent Vanheule, Rik Janssens, Daiane Boff, Anneleen Mortier, Bjorn Petri, Elzbieta Kolaczkowska, Paul Kubes, Nele BerghmansAbstract: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 (GPCR)-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 towards 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 by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not CXCL9(86-103), with similar potency. 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.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:Abstract The ELR-CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAG) and compete with functional intact chemokines for GAG binding, the longest peptide, i.e. CXCL9(74-103), being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by i.v. injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides: by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG-interactions.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:The ELR−CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74–103)) being the most potent. The COOH-terminal peptide CXCL9(74–103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74–103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74–103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74–103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions.
Nele Berghmans - One of the best experts on this subject based on the ideXlab platform.
-
cxcl9 derived peptides differentially inhibit neutrophil migration in vivo through interference with glycosaminoglycan interactions
Frontiers in Immunology, 2017Co-Authors: Vincent Vanheule, Rik Janssens, Daiane Boff, Anneleen Mortier, Bjorn Petri, Elzbieta Kolaczkowska, Paul Kubes, Nele BerghmansAbstract: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 (GPCR)-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 towards 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 by intravenous or intraperitoneal injection of CXCL9(74-103) or CXCL9(74-93), but not CXCL9(86-103), with similar potency. 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.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:Abstract The ELR-CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAG) and compete with functional intact chemokines for GAG binding, the longest peptide, i.e. CXCL9(74-103), being the most potent. The COOH-terminal peptide CXCL9(74-103) does not signal through or act as an antagonist for CXCR3, the G protein coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti inflammatory role for CXCL9(74-103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74-103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by i.v. injection of CXCL9(74-103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides: by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG-interactions.
-
the positively charged cooh terminal glycosaminoglycan binding cxcl9 74 103 peptide inhibits cxcl8 induced neutrophil extravasation and monosodium urate crystal induced gout in mice
Journal of Biological Chemistry, 2015Co-Authors: Vincent Vanheule, Mauro M Teixeira, Flávio A. Amaral, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Jo Van DammeAbstract:The ELR−CXC chemokine CXCL9 is characterized by a long, highly positively charged COOH-terminal region, absent in most other chemokines. Several natural leukocyte- and fibroblast-derived COOH-terminally truncated CXCL9 forms missing up to 30 amino acids were identified. To investigate the role of the COOH-terminal region of CXCL9, several COOH-terminal peptides were chemically synthesized. These peptides display high affinity for glycosaminoglycans (GAGs) and compete with functional intact chemokines for GAG binding, the longest peptide (CXCL9(74–103)) being the most potent. The COOH-terminal peptide CXCL9(74–103) does not signal through or act as an antagonist for CXCR3, the G protein-coupled CXCL9 receptor, and does not influence neutrophil chemotactic activity of CXCL8 in vitro. Based on the GAG binding data, an anti-inflammatory role for CXCL9(74–103) was further evidenced in vivo. Simultaneous intravenous injection of CXCL9(74–103) with CXCL8 injection in the joint diminished CXCL8-induced neutrophil extravasation. Analogously, monosodium urate crystal-induced neutrophil migration to the tibiofemural articulation, a murine model of gout, is highly reduced by intravenous injection of CXCL9(74–103). These data show that chemokine-derived peptides with high affinity for GAGs may be used as anti-inflammatory peptides; by competing with active chemokines for binding and immobilization on GAGs, these peptides may lower chemokine presentation on the endothelium and disrupt the generation of a chemokine gradient, thereby preventing a chemokine from properly performing its chemotactic function. The CXCL9 peptide may serve as a lead molecule for further development of inhibitors of inflammation based on interference with chemokine-GAG interactions.
