Identification of novel signaling mechanism for eosinophil cell death involving siglec-8

Published online: September 2017

Siglec-8 is a cell surface protein belonging to a CD33-related subfamily of sugar-binding receptors. Siglec-8 is uniquely expressed on the surface of eosinophils, mast cells and weakly on basophils, all important effector cells involved in acute and chronic allergic diseases. This makes Siglec-8 an interesting molecule to study for its cell biology and possible therapeutic targeting potential.  Although Siglec-8 activation has long been associated with eosinophil cell death, there was little information on how this occurs, especially since Siglecs are generally thought of as “inhibitory” receptors rather than being capable of “activating” cell processes like death.
In a recently published article in The Journal of Allergy and Clinical Immunology (JACI), Carroll and colleagues characterized the signaling mechanisms involved in Siglec-8 mediated death of human peripheral blood eosinophils and unexpectedly found that in IL-5 primed cells, Siglec-8 activates, rather than inhibits, a number of cellular processes.  Siglec-8 engagement by an antibody or artifical sugar structure promoted rapid changes in eosinophil attachment to surfaces via cell adhesion molecules called B2 integrins. Cell adhesion was necessary for other downstream responses required for cell death including activation of NADPH oxidase for production of reactive oxygen species.  Also surprising was that activation of certain tyrosine kinases, enzymes inside the cell that normally help keep them functioning well, were necessary to cause Siglec-8 mediated eosinophil death. These results suggest a novel pathway by which an alleged inhibitory receptor instead activates cell proceeses leading to eosinophil death.  This challanges the longstanding and pervasive concept that CD33-related Siglecs only function as inhibitory receptors on immune cells.  

The authors’ findings imply an important and specific role for Siglec-8 in facilitating eosinopil clearance from tissues during health and disease. The results also provide novel implications for the potential utility of Siglec-8 as a therapeutic target in the treatment of eosinophil-associated diseases, including chronic allergic diseases.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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