Inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates mitogen-activated protein kinase (MAPK) signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. Thus, these cis-binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.

由吞噬细胞引起的炎症病理导致许多使人衰弱的疾病，包括由于年龄相关性黄斑变性而导致的慢性疼痛和失明。唾液酸结合免疫球蛋白样凝集素 (Siglec) 家族的许多成员都是免疫抑制性受体，其激动作用是抗炎治疗的一种有吸引力的方法。在这里，我们证明合成的脂质缀合糖多肽可以插入细胞膜并以顺式方式接合 Siglec 受体，从而产生抑制信号传导。具体来说，我们构建了Siglec-9 的顺式结合激动剂，并表明它调节报告细胞系、永生化巨噬细胞和小胶质细胞系以及原代人巨噬细胞中的丝裂原激活蛋白激酶 (MAPK) 信号传导。因此，Siglecs的这些顺式结合激动剂提供了一种治疗性抑制免疫细胞反应性的方法。