Modulation of immune cell reactivity with <i>cis</i> -binding Siglec agonists

Abstract

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 <i>cis</i>, leading to inhibitory signaling. Specifically, we construct a <i>cis</i>-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 <i>cis</i>-binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.