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Int. J. Mol. Sci. 2017, 18(7), 1513; doi:10.3390/ijms18071513

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

1
Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1042, B-3000 Leuven, Belgium
2
Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av Antonio Carlos 6627, Pampulha, Belo Horizonte 31270-901, Minas Gerais, Brazil
3
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1 S6, Wilrijk B-2610, Belgium
Nicole Lamoen passed away a few months ago.
*
Author to whom correspondence should be addressed.
Received: 7 June 2017 / Revised: 3 July 2017 / Accepted: 6 July 2017 / Published: 13 July 2017
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
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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. View Full-Text
Keywords: chemokine; glycosaminoglycan; leukocyte migration; posttranslational modification; CXCR3; dipeptidyl peptidase IV; CD26 chemokine; glycosaminoglycan; leukocyte migration; posttranslational modification; CXCR3; dipeptidyl peptidase IV; CD26
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Metzemaekers, M.; Mortier, A.; Janssens, R.; Boff, D.; Vanbrabant, L.; Lamoen, N.; Van Damme, J.; Teixeira, M.M.; De Meester, I.; Amaral, F.A.; Proost, P. Glycosaminoglycans Regulate CXCR3 Ligands at Distinct Levels: Protection against Processing by Dipeptidyl Peptidase IV/CD26 and Interference with Receptor Signaling. Int. J. Mol. Sci. 2017, 18, 1513.

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