Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Department of Environmental & Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
JCI Insight. 2019 Mar 7;4(5). doi: 10.1172/jci.insight.122475.
Although type-2-induced (T2-induced) epithelial dysfunction is likely to profoundly alter epithelial differentiation and repair in asthma, the mechanisms for these effects are poorly understood. A role for specific mucins, heavily N-glycosylated epithelial glycoproteins, in orchestrating epithelial cell fate in response to T2 stimuli has not previously been investigated. Levels of a sialylated MUC4β isoform were found to be increased in airway specimens from asthmatic patients in association with T2 inflammation. We hypothesized that IL-13 would increase sialylation of MUC4β, thereby altering its function and that the β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) would regulate the sialylation. Using human biologic specimens and cultured primary human airway epithelial cells (HAECs),we demonstrated that IL-13 increases ST6GAL1-mediated sialylation of MUC4β and that both were increased in asthma, particularly in sputum supernatant and/or fresh isolated HAECs with elevated T2 biomarkers. ST6GAL1-induced sialylation of MUC4β altered its lectin binding and secretion. Both ST6GAL1 and MUC4β inhibited epithelial cell proliferation while promoting goblet cell differentiation. These in vivo and in vitro data provide strong evidence for a critical role for ST6GAL1-induced sialylation of MUC4β in epithelial dysfunction associated with T2-high asthma, thereby identifying specific sialylation pathways as potential targets in asthma.
虽然 2 型诱导（T2 诱导）上皮功能障碍可能深刻改变哮喘中的上皮分化和修复，但这些影响的机制仍知之甚少。特定粘蛋白（富含 N-糖基化的上皮糖蛋白）在协调上皮细胞命运以响应 T2 刺激方面的作用尚未得到研究。以前发现气道标本中唾液酸化 MUC4β 同工型的水平在与 T2 炎症相关的哮喘患者中增加。我们假设 IL-13 将增加 MUC4β 的唾液酸化，从而改变其功能，并且β-半乳糖苷 α-2,6-唾液酸转移酶 1（ST6GAL1）将调节唾液酸化。使用人生物学标本和培养的原代人气道上皮细胞（HAEC），我们证明 IL-13 增加了 MUC4β 的 ST6GAL1 介导的唾液酸化，并且在哮喘中均增加，特别是在 T2 生物标志物升高的痰上清液和/或新鲜分离的 HAEC 中。ST6GAL1 诱导的 MUC4β 唾液酸化改变了其凝集素结合和分泌。ST6GAL1 和 MUC4β 均抑制上皮细胞增殖，同时促进杯状细胞分化。这些体内和体外数据为 ST6GAL1 诱导的 MUC4β 唾液酸化在与 T2 高哮喘相关的上皮功能障碍中起关键作用提供了有力证据，从而确定了特定的唾液酸化途径作为哮喘的潜在靶点。
