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-E...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (22), p.8173-8178
Main Authors: Nonaka, Motohiro, Bao, Xingfeng, Matsumura, Fumiko, Götze, Sebastian, Kandasamy, Jeyakumar, Kononov, Andrew, Broide, David H., Nakayama, Jun, Seeberger, Peter H., Fukuda, Minoru
Format: Article
Language:English
Subjects:
Allergies
Animals
Antibodies
Asthma
Asthma - drug therapy
Asthma - immunology
Biological Sciences
Bronchoalveolar Lavage Fluid - immunology
Carbohydrate Sequence
Carbohydrates
Chemokine CCL20 - immunology
Chemokine CCL20 - metabolism
Chemokines
Chemotaxis - immunology
Disease Models, Animal
Eosinophils - cytology
Eosinophils - drug effects
Eosinophils - immunology
Heparin
Heparitin Sulfate - immunology
Heparitin Sulfate - metabolism
Iduronic Acid - chemical synthesis
Iduronic Acid - pharmacology
Leukocytes
Lung - immunology
Lungs
Lymphocytes
Medical treatment
Mice
Mice, Knockout
Monosaccharides
N-Acetylglucosaminyltransferases - genetics
Ovalbumin - immunology
Ovalbumin - pharmacology
Polysaccharides - immunology
Polysaccharides - metabolism
Receptor, TIE-2 - genetics
Rodents
Sulfates
Sulfates - chemical synthesis
Sulfates - pharmacology
T lymphocytes
T-Lymphocytes - cytology
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1319870111