title: The Positively Charged COOH-terminal Glycosaminoglycan-binding CXCL9(74-103) Peptide Inhibits CXCL8-induced Neutrophil Extravasation and Monosodium Urate Crystal-induced Gout in Mice.
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 (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.
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Vanheule
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Janssens
authors.affiliation: the Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil, and.
authors.forename: Daiane
authors.initials: D
authors.lastname: Boff
authors.affiliation: the Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzes Universität, 8010 Graz, Austria.
authors.forename: Nikola
authors.initials: N
authors.lastname: Kitic
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Berghmans
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ronsse
authors.affiliation: the Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Karl-Franzes Universität, 8010 Graz, Austria.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
authors.affiliation: the Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil, and.
authors.forename: Flavio Almeida
authors.initials: FA
authors.lastname: Amaral
authors.affiliation: the Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil, and.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium, paul.proost@rega.kuleuven.be.
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.affiliation: From the Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Mortier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D002464:Cell Migration Inhibition / Q000187:drug effects; D054370:Chemokine CXCL9 / Q000737:chemistry / Q000627:therapeutic use*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006025:Glycosaminoglycans / Q000276:immunology; D006073:Gout / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D014527:Uric Acid
chemical_list: D000893:Anti-Inflammatory Agents; D054370:Chemokine CXCL9; D006025:Glycosaminoglycans; D016209:Interleukin-8; D010455:Peptides; D014527:Uric Acid
keywords: chemokine; glycosaminoglycan; inflammation; migration; neutrophil