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Anti‐inflammatory effects of the GAG ‐binding CXCL 9(74‐103) peptide in dinitrofluorobenzene‐induced contact hypersensitivity in mice
Author(s) -
Vanheule Vincent,
Crijns Helena,
Poosti Fariba,
Ruytinx Pieter,
Berghmans Nele,
Gerlza Tanja,
Ronsse Isabelle,
Pörtner Noëmie,
Matthys Patrick,
Kungl Andreas J.,
Opdenakker Ghislain,
Struyf Sofie,
Proost Paul
Publication year - 2018
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.13227
Subject(s) - chemokine , chemistry , immunology , proinflammatory cytokine , ccr1 , inflammation , chemokine receptor , microbiology and biotechnology , receptor , biochemistry , biology
Summary Background To recruit leucocytes to an inflammatory site, chemokine binding to glycosaminoglycans ( GAG s) is critical. Therefore, strategies to interfere with this interaction, aiming at the production of anti‐inflammatory agents, were developed. These include production of modified chemokines without affinity for G protein‐coupled receptors but with enhanced affinity for GAG s. Such modified chemokines compete with functional chemokines for GAG binding, prevent chemokine immobilization and presentation, and inhibit leucocyte migration. In addition to modified chemokines, a GAG ‐binding peptide consisting of the 30 COOH ‐terminal residues of CXCL 9, that is CXCL 9(74‐103), inhibited CXCL 8‐ and monosodium urate crystal‐induced neutrophil migration. Objective We wanted to explore whether interference with chemokine‐ GAG interactions by CXCL 9(74‐103) reduces inflammation in neutrophil‐dependent dinitrofluorobenzene‐induced contact hypersensitivity. Methods For this study, we evaluated several inflammatory parameters, including ear swelling and the levels of chemokines, cytokines, proteases and neutrophils in the ears of dinitrofluorobenzene‐induced mice treated with CXCL 9(74‐103) or buffer. Results One intravenous injection of CXCL 9(74‐103), just before painting with dinitrofluorobenzene on the ear, did not affect protein levels of the major murine neutrophil attractant, that is CXCL 6, in this contact hypersensitivity model. However, IL ‐6, CXCL 1, CCL 2 and matrix metalloproteinase‐9 (MMP‐9) protein concentrations and peroxidase activity in challenged ears were reduced. In addition, intravenous injection of the CXCL 9‐derived peptide led to a reduced ear swelling response, indicating that the locally produced chemokines were hindered to attract leucocytes. The inhibiting potential of CXCL 9(74‐103) was explained by its competition for GAG binding with CXCL 1, CXCL 6 and CCL 3 and inhibition of transendothelial migration of neutrophils to CXCL 6. Conclusions and Clinical Relevance The CXCL 9(74‐103) peptide inhibited dinitrofluorobenzene‐induced infiltration of neutrophils and neutrophil‐dependent inflammation in ears. Therefore, CXCL 9(74‐103) may be a lead molecule for the development of therapeutic peptides or peptide derivatives that compete with functional chemokines for GAG binding.