Sialyltransferase ST3Gal-III Regulates Siglec-F Ligand Formation and Eosinophilic Lung Inflammation in Mice
Authors
Maho Suzukawa, Marina Miller, Peter Rosenthal, Jae Youn Cho, Taylor A. Doherty, Ajit Varki, and David Broide
Institution
UC San Diego
Country
United States
Year
2013
Journal
Imunology
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.