Eosinophil and mast cell Siglecs: From biology to drug target

Abstract

Mast cells and eosinophils are innate immune cells involved in both acute and chronic inflammatory responses. Siglecs are a family of cell surface receptors that share sialic acid binding activity. Over the past 20 years, our knowledge of the expression and function of Siglecs on cells of the immune system and others has greatly expanded, as has our understanding of their signaling, ligands, and possible roles in disease pathophysiology. Because of this, Siglecs have garnered interest as potential drug targets using strategies ranging from biologics to ligand‐directed nanoparticles. This mini‐review will highlight the state of our knowledge regarding human eosinophil and mast cell Siglecs, their biology, what they recognize, tools developed for in vitro and preclinical experimentation, and the status of ongoing efforts to develop drugs that engage eosinophil and mast cell Siglecs for potential therapeutic benefit.

Isolation, identification, and characterization of the human airway ligand for the eosinophil and mast cell immunoinhibitory receptor Siglec-8

“…The Siglec family of immune cell surface receptors and the extracellular sialoglycans to which they bind provide receptorligand interactions that modulate immune responses. 2 Although much has been learned about Siglecs and their potential as drug targets, 5,25 less is known about their endogenous sialoglycan ligands. Nature typically builds glycans into multivalent arrays that enhance site affinity by clustering glycans on protein carriers that in turn engage receptors with high avidity to initiate physiologic outcomes.…”

“…2 Among these, Siglec-8, which is expressed selectively on human eosinophils, mast cells, and basophils, 3,4 can significantly downregulate allergic inflammation and is under investigation as a therapeutic target in eosinophil-and mast cell-mediated diseases. 5,6 Siglecs bind to sialic acid-containing glycans (sialoglycans) on cell surfaces or are secreted into the local cellular milieu of inflammatory target tissues. Molecular recognition between Siglec-8 and its endogenous sialoglycan ligands induces immune inhibition.…”

Divergent Siglec-F(eights) of mouse and human eosinophil death

“…The ability to deplete eosinophils in mouse models has led to a significantly expanded field of research defining the diverse immune functions of eosinophils in health and disease 1 . The discovery of Siglec‐8 on human eosinophils and Siglec‐F on mouse eosinophils has opened a new door for manipulation of eosinophil survival and function 2 …”

“…Nearly every immune cell expresses one or many Siglecs. Siglec‐8 and Siglec‐F are reported as functional paralogs 2,4 . They both recognize sialosides 6′sulfo‐sialyl‐Lewis X and glycans found in the pulmonary compartment as natural ligands.…”

“…Overall, the results of the authors show that regardless of potential species differences, both mouse and human eosinophils expressing Siglec‐8 can undergo Fc‐dependent cell death in vivo, resulting in comparable readouts for antibody‐mediated killing of Siglec‐8+ eosinophils. This model is relevant for translational studies as Fc‐mediated killing is a desired activity of biologics to enhance killing of cells, such as for the humanized αSiglec‐8 hIgG1 clone AK002 in clinical trials that targets eosinophils 2 . This provides a new translational model to characterize the role of eosinophils in chronic disease phases of initiation, propagation, and resolution.…”