Siglec-9 modulates mast cell function in homeostasis and in mouse models of allergic disease 4222

Abstract Description Mast cell activation is essential in allergic disease development. Engaging Sialic acid-binding immunoglobin-like lectins (Siglecs) such as CD33, Siglec-6, -7 and -8 has been shown to inhibit mast cell activation. We have identified Siglec-9 as a functional Siglec on human mast cells, leading us to investigate its role in modulating mast cell activation in homeostasis and allergic disease. To examine Siglec-9’s effect on mast cell activation in vivo, we generated transgenic mice expressing human Siglec-9 exclusively in mast cells (Cpa3-Cre+; hSiglec-9+). These mice displayed reduced LAMP-1 surface expression and lower serum mast cell protease-1 levels, indicative of decreased spontaneous mast cell degranulation. Following sensitization and challenge with house dust mite (HDM), Cpa3-Cre+; hSiglec-9+ mice, but not mice expressing human Siglec-8 on their mast cells, exhibited diminished allergic airway pathology. Mice expressing Siglec-9 in myeloid cells were not protected from HDM-induced disease. Additionally, liposomes displaying synthetic Siglec-9 ligand reduced passive systemic anaphylaxis in mice with global Siglec-7/9 expression, without impairing immune response to systemic Staphylococcus aureus infection. Our findings suggest Siglec-9 mitigates allergic disease by modulating mast cell function and thus presents a potential target for treatment. Funding Sources Supported by seed funds from Seattle Children’s Research Institute. Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)