Airway glycomic and allergic inflammatory consequences resulting from keratan sulfate galactose 6-O-sulfotransferase (CHST1) deficiency

作者：Kumagai Tadahiro; Kiwamoto Takumi; Brummet Mary E; Wu Fan; Aoki Kazuhiro; Zhu Zhou; Bochner Bruce S; Tiemeyer Michael^*

来源：Glycobiology, 2018, 28(6): 406-417.

DOI：10.1093/glycob/cwy025

• asthma
• CHST1
• eosinophils
• O-glycan
• Siglec-F

Siglec-F is a pro-apoptotic receptor on mouse eosinophils that recognizes 6'-sulfated sialyl Lewis X and 6'-sulfated sialyl N-acetyl-lactosamine as well as multivalent sialyl N-acetyl-lactosamine structures on glycan arrays. We hypothesized that attenuation of the carbohydrate sulfotransferase 1 (CHST1) gene encoding keratan sulfate galactose 6-O-sulfotransferase, an enzyme likely required for 6'-sulfation of some of these putative Siglec-F glycan ligands, would result in decreased Siglec-F lung ligand levels and enhanced allergic eosinophilic airway inflammation. Tissue analysis detected CHST1 expression predominantly not only in parenchymal cells but not in airway epithelium, the latter being a location where Siglec-F ligands are located. Western blotting of lung extracts with Siglec-F-Fc fusion proteins detected approximate to 500 kDa and approximate to 200 kDa candidate Siglec-F ligands that were not appreciably altered in CHST1(-/-) lungs compared with normal mouse lungs. Characterization of the O-linked glycans of lung tissue and bronchoalveolar lavage fluid detected altered sialylation but minimal change in sulfation. Eosinophilic airway inflammation was induced in wild-type (WT) and CHST1(-/-) mice via sensitization to ovalbumin (OVA) and repeated airway challenge. After OVA sensitization and challenge, Siglec-F ligands on airway cells, and numbers of eosinophils and neutrophils accumulating in the airways, both increased to a similar degree in WT and CHST1(-/-) mouse lungs, while macrophages and lymphocytes increased significantly more in CHST1(-/-) mouse airway compared with normal mouse lungs. Therefore, keratan sulfate galactose 6-O-sulfotransferase does not contribute to the synthesis of glycan ligands for Siglec-F in the airways, although its absence results in exaggerated accumulation of airway macrophages and lymphocytes.

• 出版日期2018-6
• 单位西北大学