Interactions between Siglec-8 and endogenous sialylated cis ligands restrain cell death induction in human eosinophils and mast cells.

Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a sialoside-binding receptor expressed by eosinophils and mast cells that exhibits priming status- and cell type-dependent inhibitory activity. On eosinophils that have been primed with IL-5, GM-CSF, or IL-33, antibody ligation of Siglec-8 induces cell death through a pathway involving the β2 integrin-dependent generation of reactive oxygen species (ROS) via NADPH oxidase. In contrast, Siglec-8 engagement on mast cells inhibits cellular activation and mediator release but reportedly does not impact cell viability. The differences in responses between cytokine-primed and unprimed eosinophils, and between eosinophils and mast cells, to Siglec-8 ligation are not understood. We previously found that Siglec-8 binds to sialylated ligands present on the surface of the same cell (so-called cis ligands), preventing Siglec-8 ligand binding in trans. However, the functional relevance of these cis ligands has not been elucidated. We therefore explored the potential influence of cis ligands of Siglec-8 on both eosinophils and mast cells. De-sialylation using exogenous sialidase profoundly altered the consequences of Siglec-8 antibody engagement on both cell types, eliminating the need for cytokine priming of eosinophils to facilitate cell death and enabling Siglec-8-dependent mast cell death without impacting anti-Siglec-8 antibody binding. The cell death process licensed by de-sialylation resembled that characterized in IL-5-primed eosinophils, including CD11b upregulation, ROS production, and the activities of Syk, PI3K, and PLC. These results implicate cis ligands in restraining Siglec-8 function on eosinophils and mast cells and reveal a promising approach to the selective depletion of mast cells in patients with mast cell-mediated diseases.

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Copyright © 2023 Cao, Rische, Bochner and O’Sullivan.

Déclaration de conflit d'intérêts

Author BB receives remuneration for serving on the scientific advisory board of Allakos, Inc. and owns stock in Allakos. He has served as a consultant for GSK, Third Harmonic Bio, Lupagen, Acelyrin, and Sanofi/Regeneron, and receives publication-related royalty payments from Elsevier and UpToDate®. He is a co-inventor on existing Siglec-8–related patents and thus may be entitled to a share of royalties received by Johns Hopkins University during development and potential sales of such products. Author BB is also a co-founder of Allakos, which makes him subject to certain restrictions under University policy. The terms of this arrangement are being managed by Johns Hopkins University and Northwestern University in accordance with their conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.