Siglec‐8 on human eosinophils and mast cells, and Siglec‐F on murine eosinophils, are functionally related inhibitory receptors

Abstract

Siglecs (sialic acid‐binding, Ig‐like lectins) are a family of single‐pass transmembrane cell surface proteins found predominantly on leucocytes. Their unique structural characteristics include an N‐terminal carbohydrate‐binding (‘lectin’) domain that binds sialic acid, followed by a variable number of Ig‐like domains, hence these structures are a subset of the Ig gene superfamily. Another unique feature of Siglecs is that most, but not all, possess so‐called immunoreceptor tyrosine‐based inhibitory motifs in their cytoplasmic domains, suggesting that these molecules function in an inhibitory capacity. Siglec‐8, the eighth member identified at the time, was discovered as part of an effort initiated almost a decade ago to identify novel human eosinophil and mast cell proteins. Since that time, its selective expression on human eosinophils and mast cells has been confirmed. On eosinophils, Siglec‐8 engagement results in apoptosis, whereas on mast cells, inhibition of FcɛRI‐dependent mediator release, without apoptosis, is seen. It has subsequently been determined that the closest functional paralog in the mouse is Siglec‐F, selectively expressed by eosinophils but not expressed on mast cells. Despite only modest homology, both Siglec‐8 and Siglec‐F preferentially recognize a sulphated glycan ligand closely related to sialyl Lewis X, a common ligand for the selectin family of adhesion molecules. Murine experiments in normal, Siglec‐F‐deficient mice and hypereosinophilic mice have resulted in similar conclusions that Siglec‐F, like Siglec‐8, plays a distinctive and important role in regulating eosinophil accumulation and survival in vivo. Given the resurgent interest in eosinophil‐directed therapies for a variety of disorders, plus its unique additional ability to also target the mast cell, therapies focusing on Siglec‐8 could some day prove to be a useful adjunct to our current armamentarium for the treatment of asthma, allergies and related disorders where overproduction and overactivity of eosinophils and mast cells is occurring.