Immunoregulatory Siglec ligands are abundant in human and mouse aorta and are up-regulated by high glucose
Immunoregulatory Siglec ligands are abundant in human and mouse aorta and are up-regulated by high glucose
复制标题
免疫调节 Siglec 配体在人类和小鼠主动脉中含量丰富，并会因高葡萄糖而上调
DOI：
10.1016/j.lfs.2018.11.049
复制
发表时间：
2019
期刊：
影响因子：
6.1
通讯作者：
Jia Yi
中科院分区：
文献类型：
--
作者：
Zhang Yingxian;Zheng Yu;Li Jin;Nie Ling;Hu Yijie;Wang Fangjie;Liu Hongmei;Fern;es Steve M;Zhong Qianjin;Li Xiaohui;Schnaar Ronald L;Jia Yi
目的炎症是动脉粥样硬化发展的驱动力，高血糖是血管病变的重要危险因素。Siglec-9，在人中性粒细胞和巨噬细胞上表达，结合组织上的特异性聚糖配体以减轻持续的炎症。材料和方法表征人主动脉上的Siglec-9配体，以及高糖暴露对人脐静脉内皮细胞上Siglec-9配体表达的影响Siglec-9配体在人主动脉和HUV-EC-C上广泛表达。在体外高糖暴露下，HUV-EC-C上的Siglec-9配体急剧上调，高血糖小鼠腹部的Siglec-E配体也是如此。HUV-EC-C暴露于高糖导致共培养的巨噬细胞中一致的抑制性变化，包括凋亡增加和吞噬作用降低。HUV-EC-C上Siglec-9配体表达的控制是参与其生物合成的酶UDP-半乳糖-4-差向异构酶（GALE）的变化和增加的细胞N-乙酰半乳糖胺的下游。结果表明，高糖暴露可导致GALE和GalNAc表达改变下游的主动脉和HUV-EC-C细胞上的免疫抑制性Siglec-9唾液酸聚糖配体表达上调，从而导致巨噬细胞凋亡上调和吞噬活性降低。血管内皮细胞上Siglec-9唾液酸聚糖配体表达的变化可能是对动脉粥样硬化初始步骤的自然反应，并且可能是调节糖尿病血管病炎症的潜在靶点。
AimInflammation is a driving force in development of atherosclerosis, and hyperglycemia is a significant risk factor for angiopathy. Siglec-9, expressed on human neutrophils and macrophages, engages specific glycan ligands on tissues to diminish ongoing inflammation.Materials and methodSiglec-9 ligands on human aorta were characterized and the effects of high glucose exposure on the expression of ligands for Siglec-9 on human umbilical vein endothelial cells (HUV-EC-C) in vitro and ligands for the comparable siglec (Siglec-E) on mouse aorta in vivo were studied.Key findingsSiglec-9 ligands were expressed broadly on human aorta, as well as on HUV-EC-C. Siglec-9 ligands on HUV-EC-C were sharply up-regulated under high glucose exposure in vitro, as were Siglec-E ligands on the aortas of hyperglycemic mice. Exposure of HUV-EC-C to high-glucose resulted in consistent inhibitory changes in co-cultured macrophages including increased apoptosis and decreased phagocytosis. Control of Siglec-9 ligand expression on HUV-EC-C was downstream of changes in an enzyme involved in their biosynthesis, UDP-galactose-4-epimerase (GALE) and increased cellularN-acetylgalactosamine. The alteration of GALE was associated with the regulatory microRNA hsa-let-7f.SignificanceWe conclude that exposure to high-glucose results in up-regulation of immune inhibitory Siglec-9 sialoglycan ligands on aorta and HUV-EC-C cells downstream of altered GALE and GalNAc expression, resulting in up-regulation of apoptosis and decrease of phagocytic activity of macrophages. Changes in Siglec-9 sialoglycan ligand expression on vascular endothelial cells may be a natural response to the initial steps of atherosclerosis and might be a potential target to regulate inflammation in diabetic angiopathy.