Siglec-8 is a member of the CD33 sialic acid-bind immunoglobulin-like lectin (Siglec) family found only on human mast cells, eosinophils and basophils. This transmembrane protein has an extracellular domain that recognizes specific carbohydrate molecules (glycans), and intracellular tyrosine-based inhibition motifs that putatively converts receptor binding into immune suppression. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs. Mouse Siglec-F is expressed predominantly on mouse eosinophils. Incubation of human eosinophils with specific Siglec-8 antibodies, or mouse eosinophils with Siglec-F antibodies, induces apoptosis, and dosing of mice with Siglec-F antibodies reduces eosinophil numbers. In contrast, Siglec-8 engagement on human mast cells by antibodies in vitro does not induce apoptosis but does inhibit mediator release induced via FceRI activation. Both Siglec-8 and Siglec-F bind a unique glycan ligand referred to as 6'-sulfo-sLex, or NeuAca2-3(6-O-sulfo)Ga1S1-4[Fuca1-3]G1cNAc. Therefore, activation of Siglec-8/Siglec-F through its natural glycan ligand, or through antibodies or glycomimetic agonists, may provide a novel means to specifically inhibit and/or deplete eosinophils and mast cells, thereby reducing allergic inflammatory responses. We thus hypothesize that: (i) Siglec-8/Siglec-F on the surface of allergic inflammatory cells binds to its natural carbohydrate ligands, expressed on tissues, to limit allergic inflammation by activating a negative signaling pathway;(ii) Allergic inflammation in vivo can be controlled by regulating expression of natural Siglec-8 ligands in tissues;and (iii) Siglec-8/Siglec-F mAbs or synthetic molecules based on the structure of their ligands (glycomimetics) will be capable of interrupting allergic inflammation. These concepts will be explored through four specific aims.
Aim 1 will characterize natural Siglec-8/Siglec-F ligands and determine their tissue expression.
Aim 2 will determine the ability of Siglec- 8/Siglec-F ligand mimetics to limit allergic responses in eosinophils and mast cells in vitro.
Aim 3 will explore the ability of mAbs or ligand mimetics to limit allergic responses in vivo, and Aim 4 will identify mechanisms by which Siglec-8 engagement induces eosinophil apoptosis and inhibits mast cell mediator release. Our proposed work on Siglec-8/Siglec-F should identify new therapeutic approaches for the treatment of diseases characterized by increased numbers of, or mediators from, eosinophils, basophils and mast cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072265-04
Application #
7908892
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Dong, Gang
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$398,189
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Bolden, Jessica E; Lucas, Erin C; Zhou, Geyu et al. (2018) Identification of a Siglec-F+ granulocyte-macrophage progenitor. J Leukoc Biol 104:123-133

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