Glycosaminoglycans Regulate CXCR3 Ligands at Distinct Levels: Protection against Processing by Dipeptidyl Peptidase IV/CD26 and Interference with Receptor Signaling

Mieke Metzemaekers, Anneleen Mortier, Rik Janssens, Daiane Boff, Lotte Vanbrabant, Nicole Lamoen, Jo Van Damme, Mauro M Teixeira, Ingrid De Meester, Flávio A Amaral, Paul Proost

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

CXC chemokine ligand (CXCL)9, CXCL10 and CXCL11 direct chemotaxis of mainly T cells and NK cells through activation of their common CXC chemokine receptor (CXCR)3. They are inactivated upon NH₂-terminal cleavage by dipeptidyl peptidase IV/CD26. In the present study, we found that different glycosaminoglycans (GAGs) protect the CXCR3 ligands against proteolytic processing by CD26 without directly affecting the enzymatic activity of CD26. In addition, GAGs were shown to interfere with chemokine-induced CXCR3 signaling. The observation that heparan sulfate did not, and heparin only moderately, altered CXCL10-induced T cell chemotaxis in vitro may be explained by a combination of protection against proteolytic inactivation and altered receptor interaction as observed in calcium assays. No effect of CD26 inhibition was found on CXCL10-induced chemotaxis in vitro. However, treatment of mice with the CD26 inhibitor sitagliptin resulted in an enhanced CXCL10-induced lymphocyte influx into the joint. This study reveals a dual role for GAGs in modulating the biological activity of CXCR3 ligands. GAGs protect the chemokines from proteolytic cleavage but also directly interfere with chemokine-CXCR3 signaling. These data support the hypothesis that both GAGs and CD26 affect the in vivo chemokine function.

Original languageEnglish
Article number1513
Pages (from-to)1513-1513
JournalInternational Journal of Molecular Sciences
Volume18
Issue number7
DOIs
Publication statusPublished - 13 Jul 2017

Keywords

  • CD26
  • chemokine
  • CXCR3
  • Dipeptidyl peptidase IV
  • Glycosaminoglycan
  • Leukocyte migration
  • Posttranslational modification

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