Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites.
Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. Here, we first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1(iKO)) mice. We showed that heparan sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. Our glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, we identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential inhibitor for CCL20-heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vain or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine-heparan sulfate interaction in the asthma development and Di-S-IdoA as a potential drug for asthma treatment.
Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
Motohiro
M
Nonaka
Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;
Xingfeng
X
Bao
Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037;Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, 14476 Potsdam, Germany;
Fumiko
F
Matsumura
Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, 14476 Potsdam, Germany;Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany;
Sebastian
S
Götze
Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, 14476 Potsdam, Germany;Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany;
Jeyakumar
J
Kandasamy
Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, 14476 Potsdam, Germany;
Andrew
A
Kononov
Department of Medicine, University of California, San Diego, La Jolla, CA 92093; and.
David H
DH
Broide
Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.
Jun
J
Nakayama
Department of Biomolecular Systems, Max Planck Institute for Colloids and Interfaces, 14476 Potsdam, Germany;Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany;
Peter H
PH
Seeberger
Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; minoru@sanfordburnham.org.
Minoru
M
Fukuda
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002240:Carbohydrate Sequence; D054418:Chemokine CCL20 / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006497:Heparan Sulfate / Q000276:immunology / Q000378:metabolism; D007067:Iduronic Acid / Q000138:chemical synthesis / Q000494:pharmacology*; D008168:Lung / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011134:Polysaccharides / Q000276:immunology / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics; D013431:Sulfates / Q000138:chemical synthesis / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000099058:Exostosin 1
D054418:Chemokine CCL20; D006497:Heparan Sulfate; D007067:Iduronic Acid; D017351:N-Acetylglucosaminyltransferases; D010047:Ovalbumin; D011134:Polysaccharides; D042787:Receptor, TIE-2; D013431:Sulfates; D000099058:Exostosin 1; C493447:CCL20 protein, mouse; C079086:Tek protein, mouse
lymphocyte recruitment; sulfated monosaccharide