The Positively Charged COOH-terminal Glycosaminoglycan-binding CXCL9(74-103) Peptide Inhibits CXCL8-induced Neutrophil Extravasation and Monosodium Urate Crystal-induced Gout in Mice

Vincent Vanheule, Rik Janssens, Daiane Boff, Nikola Kitic, Nele Berghmans, Isabelle Ronsse, Andreas J Kungl, Flavio Almeida Amaral, Mauro Martins Teixeira, Jo Van Damme, Paul Proost, Anneleen Mortier

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45 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)21292-21304
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number35
DOIs
Publication statusPublished - 28 Aug 2015

Bibliographical note

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Keywords

  • Amino Acid Sequence
  • Animals
  • Anti-Inflammatory Agents/chemistry
  • Cell Migration Inhibition/drug effects
  • Chemokine CXCL9/chemistry
  • Chemotaxis, Leukocyte/drug effects
  • Glycosaminoglycans/immunology
  • Gout/chemically induced
  • Humans
  • Interleukin-8/antagonists & inhibitors
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neutrophils/cytology
  • Peptides/chemistry
  • Uric Acid

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