Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice.

Abstract

Sialic acid-binding, Ig-like lectin (Siglec)-F is highly expressed on mouse eosinophils and plays an important role in regulating levels of eosinophilic lung inflammation. In this study we investigated the mechanism of constitutive and inducible Siglec-F ligand expression by lung airway epithelial cells and inflammatory cells in wild-type (WT) and genetically altered mice (ST3Gal-III heterozygotes, Fuc-TIV/VII double null, STAT6 null). Flow cytometry demonstrated that Siglec-F ligands are constitutively expressed in vitro and in vivo in selected lung cell types (epithelial cells, eosinophils, macrophages, and mast cells, but not CD4, CD8, or B cells) and are induced in response to divergent stimuli, including innate stimuli (TLR ligands, Alternaria), Th2 cytokines (IL-4, IL-13), and adaptive immune stimuli (OVA allergen). Furthermore, studies of deficient mice demonstrated the greater importance of the sialyltransferase ST3Gal-III compared with fucosyltransferases Fuc-TIV/VII in the synthesis of the constitutive and inducible Siglec-F ligands by lung epithelial and nonepithelial cells. In keeping with this, ST3Gal-III heterozygote mice (deficient in expression of Siglec-F ligands) also had significantly enhanced OVA-induced eosinophilic airway inflammation associated with reduced eosinophil apoptosis. Reduced eosinophil apoptosis in the lung of ST3Gal-III-deficient mice is likely mediated by reduced epithelial expression of Siglec-F ligands as WT eosinophils (which highly express Siglec-F) cultured with ST3Gal-III-deficient epithelial cells (which do not express Siglec-F ligand) showed reduced eosinophil apoptosis compared with WT eosinophils cultured with WT epithelial cells. Overall, these studies demonstrate that ST3Gal-III plays an important role in Siglec-F ligand formation and eosinophil apoptosis with resultant effects on eosinophilic inflammation in the lung.

• Authors: Maho Suzukawa, Marina Miller, Peter Rosenthal, Jae Youn Cho, Taylor A Doherty, Ajit Varki, David Broide
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 12 Pg. 5939-48 (Jun 15 2013) ISSN: 1550-6606 [Electronic] United States
• PMID: 23677475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, Myelomonocytic
• Sialic Acid Binding Immunoglobulin-like Lectins
• Siglecf protein, mouse
• Sialyltransferases
• beta-Galactoside alpha-2,3-Sialyltransferase

Topics

• Animals
• Antigens, Differentiation, Myelomonocytic (immunology, metabolism)
• Apoptosis (immunology)
• Cell Separation
• Eosinophilia (immunology, metabolism)
• Eosinophils (immunology, metabolism)
• Epithelial Cells (immunology, metabolism)
• Flow Cytometry
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pneumonia (immunology, metabolism)
• Polymerase Chain Reaction
• Sialic Acid Binding Immunoglobulin-like Lectins
• Sialyltransferases (immunology, metabolism)
• beta-Galactoside alpha-2,3-Sialyltransferase