Airway glycomic and allergic inflammatory consequences resulting from keratan sulfate galactose 6-O-sulfotransferase (CHST1) deficiency
Airway glycomic and allergic inflammatory consequences resulting from keratan sulfate galactose 6-O-sulfotransferase (CHST1) deficiency
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DOI：
10.1093/glycob/cwy025
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发表时间：
2018-06-01
期刊：
影响因子：
4.3
通讯作者：
Tiemeyer, Michael
中科院分区：
文献类型：
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作者：
Kumagai, Tadahiro;Kiwamoto, Takumi;Tiemeyer, Michael
Siglec-F是小鼠嗜酸性粒细胞上的促凋亡受体，其识别聚糖阵列上的6 '-硫酸化唾液酸刘易斯X和6'-硫酸化唾液酸N-乙酰基-乳糖胺以及多价唾液酸N-乙酰基-乳糖胺结构。我们假设，编码硫酸角质素半乳糖6-O-磺基转移酶的碳水化合物磺基转移酶1（CHST 1）基因（一种可能是这些推定的Siglec-F聚糖配体中的一些6 '-硫酸化所需的酶）的减弱将导致Siglec-F肺配体水平降低和过敏性嗜酸性粒细胞气道炎症增强。组织分析检测到CHST 1表达主要不仅在实质细胞中，而且不在气道上皮中，后者是Siglec-F配体所在的位置。用Siglec-F-Fc融合蛋白对肺提取物进行蛋白质印迹，检测到约500 kDa和约200 kDa的候选Siglec-F配体，与正常小鼠肺相比，这些配体在CHST 1（-/-）肺中没有明显改变。肺组织和支气管肺泡灌洗液的O-连接聚糖表征检测到唾液酸化改变，但硫酸化变化极小。在野生型（WT）和CHST 1（-/-）小鼠中，通过致敏卵清蛋白（OVA）和反复气道激发诱导嗜酸性气道炎症。在OVA致敏和激发后，气道细胞上的Siglec-F配体以及气道中积聚的嗜酸性粒细胞和嗜中性粒细胞的数量在WT和CHST 1（-/-）小鼠肺中均增加至相似程度，而与正常小鼠肺相比，CHST 1（-/-）小鼠气道中的巨噬细胞和淋巴细胞显著增加更多。因此，硫酸角质素半乳糖6- 0-磺基转移酶不促进气道中Siglec-F的聚糖配体的合成，尽管其缺乏导致气道巨噬细胞和淋巴细胞的过度积聚。
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.