Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina.
Polysialic acid blocks mononuclear phagocyte reactivity, inhibits complement activation, and protects from vascular damage in the retina.
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DOI：
10.15252/emmm.201606627
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发表时间：
2017-02
影响因子：
11.1
通讯作者：
Neumann H
中科院分区：
文献类型：
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作者：
Karlstetter M;Kopatz J;Aslanidis A;Shahraz A;Caramoy A;Linnartz-Gerlach B;Lin Y;Lückoff A;Fauser S;Düker K;Claude J;Wang Y;Ackermann J;Schmidt T;Hornung V;Skerka C;Langmann T;Neumann H
年龄相关性黄斑变性（AMD）是老年人群失明的主要原因。其病理生理学与活性氧（ROS）和补体系统的激活有关。唾液酸聚合物通过抑制性唾液酸结合免疫球蛋白样凝集素-11（SIGLEC 11）受体阻止人单核吞噬细胞产生ROS。在这里，我们表明，在单核吞噬细胞上表达SIGLEC 11的人源化转基因小鼠中，低剂量玻璃体内注射平均聚合度为20的低分子量聚唾液酸（polySia avDP 20）降低了它们的反应性和激光凝固诱导的血管渗漏。此外，polySia avDP 20阻止了SIGLEC 11转基因和野生型动物中膜攻击复合物的沉积。在体外，polySia avDP 20对先天免疫系统显示出两种独立但协同的作用。首先，polySia avDP 20阻止肿瘤坏死因子-α、血管内皮生长因子A和SIGLEC 11阳性吞噬细胞产生超氧化物。其次，polySia avDP 20直接干扰补体激活。我们的数据提供了证据表明，polySia avDP 20改善了视网膜中的激光诱导的损伤，因此是预防AMD相关炎症和血管生成的有希望的候选药物。
Age‐related macular degeneration (AMD) is a major cause of blindness in the elderly population. Its pathophysiology is linked to reactive oxygen species (ROS) and activation of the complement system. Sialic acid polymers prevent ROS production of human mononuclear phagocytes via the inhibitory sialic acid‐binding immunoglobulin‐like lectin‐11 (SIGLEC11) receptor. Here, we show that low‐dose intravitreal injection of low molecular weight polysialic acid with average degree of polymerization 20 (polySia avDP20) in humanized transgenic mice expressing SIGLEC11 on mononuclear phagocytes reduced their reactivity and vascular leakage induced by laser coagulation. Furthermore, polySia avDP20 prevented deposition of the membrane attack complex in both SIGLEC11 transgenic and wild‐type animals. In vitro, polySia avDP20 showed two independent, but synergistic effects on the innate immune system. First, polySia avDP20 prevented tumor necrosis factor‐α, vascular endothelial growth factor A, and superoxide production by SIGLEC11‐positive phagocytes. Second, polySia avDP20 directly interfered with complement activation. Our data provide evidence that polySia avDP20 ameliorates laser‐induced damage in the retina and thus is a promising candidate to prevent AMD‐related inflammation and angiogenesis.