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 ≈500 kDa and ≈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.

中文翻译：

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硫酸角质素半乳糖 6-O-磺基转移酶 (CHST1) 缺乏导致的气道血糖和过敏性炎症后果


Siglec-F 是小鼠嗜酸性粒细胞上的促凋亡受体，可识别 6'-硫酸化唾液酸 Lewis X 和 6'-硫酸化唾液酸N-乙酰基-乳糖胺以及聚糖阵列上的多价唾液酸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 ( CHST1 ) 基因的减弱会导致 Siglec-F 减少，该酶可能是某些假定的 Siglec-F 聚糖配体 6'-硫酸化所需的酶。肺配体水平和增强的过敏性嗜酸性粒细胞气道炎症。组织分析检测到CHST1不仅主要在实质细胞中表达，而且不在气道上皮中表达，气道上皮是 Siglec-F 配体所在的位置。使用 Siglec-F-Fc 融合蛋白对肺提取物进行蛋白质印迹检测，检测到约 500 kDa 和约 200 kDa 候选 Siglec-F 配体，与正常小鼠肺相比，这些配体在CHST1 ^{- / -}肺中没有明显改变。肺组织和支气管肺泡灌洗液的 O 连接聚糖的表征检测到唾液酸化改变，但硫酸化变化最小。通过对卵清蛋白 (OVA) 致敏和重复气道激发，在野生型 (WT) 和CHST1 ^{− / −}小鼠中诱导嗜酸性粒细胞气道炎症。 OVA致敏和激发后，WT和CHST1 ^{- / -}小鼠肺中气道细胞上的Siglec-F配体以及气道中积聚的嗜酸性粒细胞和中性粒细胞数量均增加至相似程度，而CHST1中巨噬细胞和淋巴细胞的增加显着更多^{− / −}小鼠气道与正常小鼠肺部的比较。因此，硫酸角质素半乳糖 6- O-磺基转移酶不会促进气道中 Siglec-F 聚糖配体的合成，尽管它的缺失会导致气道巨噬细胞和淋巴细胞的过度积累。