Department of Chemistry, Stanford University, Stanford, CA 94305.
Stanford ChEM-H, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2012408118.
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 , leading to inhibitory signaling. Specifically, we construct a -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 -binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.
吞噬细胞引起的炎症病理会导致多种使人虚弱的疾病，包括与年龄相关的黄斑变性引起的慢性疼痛和失明。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受体，其激动剂是一种有吸引力的抗炎治疗方法。在这里，我们表明，合成脂质缀合的糖肽可以插入细胞膜并与 Siglec 受体结合，从而导致抑制性信号传导。具体来说，我们构建了 Siglec-9 的配体，并表明它可调节报告细胞系、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活化蛋白激酶（MAPK）信号传导。因此，这些 Siglec 的配体为抑制免疫细胞反应性提供了一种治疗方法。
