title: 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.affiliation: Department of Medicine, University of California San Diego, San Diego, CA 92093, USA.
authors.forename: Maho
authors.initials: M
authors.lastname: Suzukawa
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: David
authors.initials: D
authors.lastname: Broide
mesh_terms: D000818:Animals; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D002469:Cell Separation; D004802:Eosinophilia / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D012799:Sialyltransferases / Q000276:immunology* / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D015214:Antigens, Differentiation, Myelomonocytic; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C443130:Siglecf protein, mouse; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase