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

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, 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.

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