The role of lung epithelial ligands for Siglec-8 and Siglec-F in eosinophilic inflammation.
The role of lung epithelial ligands for Siglec-8 and Siglec-F in eosinophilic inflammation.
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DOI：
10.1097/aci.0b013e32835b594a
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发表时间：
2013-02
影响因子：
2.8
通讯作者：
Bochner BS
中科院分区：
文献类型：
--
作者：
Kiwamoto T;Katoh T;Tiemeyer M;Bochner BS
Siglec-8和Siglec-F是分别在人和小鼠嗜酸性粒细胞表面上发现的单次跨膜抑制性受体，但对其生理性聚糖配体知之甚少。本文回顾了关于这一主题的最新知识，并概述了用于进一步确定这些分子在肺中的产生和糖生化性质的策略。Siglec-8和Siglec-F识别相同的聚糖结构，即6′-硫酸化唾液酸刘易斯X，如使用聚糖阵列技术测定的。研究已经鉴定了定位于组织切片中小鼠气道上皮的α 2，3-连接唾液酸化糖蛋白结构，其中它们的组成性表达需要特异性唾液酸转移酶St 3gal 3。这些配体在肺中的表达在变应性炎症期间和通过细胞因子如IL-13增强，并且维持在小鼠肺上皮的原代气-液界面培养物中。进一步的表征表明它们是高分子量的唾液酸化蛋白质，脓毒症粘蛋白。通过结合分析糖组学、糖蛋白质组学图谱和进一步的体外嗜酸性粒细胞实验，包括候选结构增强嗜酸性粒细胞凋亡的能力，对生产性Siglec-8和Siglec-F接合的结构要求的精细详细的理解应该很快就会出现。加强对Siglec-F、Siglec-8及其配体的理解，应能提高我们对内源性肺途径的理解，这些途径限制了哮喘等疾病中气道内嗜酸性粒细胞的存活。对这种生物学的了解也可能为涉及选择性结合Siglec-8并诱导嗜酸性粒细胞死亡的聚糖和糖模拟物的药物开发带来新的机会。
Siglec-8 and Siglec-F are single pass transmembrane inhibitory receptors found on the surface of human and mouse eosinophils, respectively, but very little is known about their physiologic glycan ligands. This article reviews the latest knowledge on this topic and outlines the strategies being used to further define the production and glycobiochemical nature of these molecules in the lung. Both Siglec-8 and Siglec-F recognize the same glycan structure, namely 6′-sulfated sialyl Lewis X, as determined using glycan array technologies. Studies have identified α2,3-linked sialylated glycoprotein structures localized to mouse airway epithelium in tissue sections, where their constitutive expression requires the specific sialyltransferase St3gal3. Expression of these ligands in lung is enhanced during allergic inflammation and by cytokines such as IL-13, and is maintained in primary air–liquid interface cultures of mouse lung epithelium. Further characterization suggests that they are high molecular weight sialylated proteins, putatively mucins. By combining analytic glycomics, glycoproteomic mapping, and further in-vitro eosinophil experimentation including the ability of candidate structures to enhance eosinophil apoptosis, a finely detailed appreciation of the structural requirements for productive Siglec-8 and Siglec-F engagement should soon emerge. An enhanced understanding of Siglec-F, Siglec-8, and their ligands should improve our understanding of endogenous lung pathways limiting the survival of eosinophils within the airway in diseases such as asthma. Knowledge of this biology may also result in novel opportunities for drug development involving glycans and glycomimetics that selectively bind to Siglec-8 and induce eosinophil death.