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

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 FcεRI-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.