Mice deficient in the St3gal3 gene product alpha 2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation

• Type of Material: Article
• Authors: Takumi Kiwamoto, Johns Hopkins University; Mary E. Brummet, Johns Hopkins University; Fan Wu, Johns Hopkins University; Mary G. Motari, Johns Hopkins University; David Smith, Emory University; Ronald L. Schnaar, Johns Hopkins University; Zhou Zhu, Johns Hopkins University; Bruce S. Bochner, Johns Hopkins University
• Language: English
• Date: 2014-01-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 American Academy of Allergy, Asthma & Immunology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2013.05.018
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• ISSN: 0091-6749
• Volume: 133
• Issue: 1
• Start Page: 240
• End Page: +
• Grant/Funding Information: Supported by grants AI72265 and HL107151 from the National Institutes of Health.
• Keywords: MAST-CELLS; Science & Technology; Eosinophils; APOPTOSIS; lung; Immunology; MECHANISM; Siglec-F; EXPRESSION; glycan ligands; asthma; Life Sciences & Biomedicine; LIGANDS; 6 '-sulfated sialyl N-acetyl-D-lactosamine; Allergy; 6 '-sulfated sialyl Lewis X; apoptosis; SIGLEC-F; St3gal3
• Research Categories: Chemistry, Biochemistry; Health Sciences, Immunology

Abstract

Background: Sialic acid-binding immunoglobulin-like lectin (Siglec)-F is a proapoptotic receptor on mouse eosinophils, but little is known about its natural tissue ligand. Objective: We previously reported that the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) is required for constitutive Siglec-F lung ligand synthesis. We therefore hypothesized that attenuation of ST3Gal-III will decrease Siglec-F ligand levels and enhance allergic eosinophilic airway inflammation. Methods: C57BL/6 wild-type mice and St3gal3 heterozygous or homozygous deficient (St3gal3+/- and St3gal3 -/-) mice were used. Eosinophilic airway inflammation was induced through sensitization to ovalbumin (OVA) and repeated airway OVA challenge. Siglec-F human IgG1 fusion protein (Siglec-F-Fc) was used to detect Siglec-F ligands. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for inflammation, as well as various cytokines and chemokines. Serum was analyzed for allergen-specific immunoglobulin levels. Results: Western blotting with Siglec-F-Fc detected approximately 500-kDa and approximately 200-kDa candidate Siglec-F ligands that were less abundant in St3gal3 +/- lung extracts and nearly absent in St3gal3-/- lung extracts. After OVA sensitization and challenge, Siglec-F ligands were increased in wild-type mouse lungs but less so in St3gal3 mutants, whereas peribronchial and BALF eosinophil numbers were greater in the mutants, with the following rank order: St3gal3-/- ≥ St3gal3+/- > wild-type mice. Levels of various cytokines and chemokines in BALF were not significantly different among these 3 types of mice, although OVA-specific serum IgG 1 levels were increased in St3gal3-/- mice. Conclusions: After OVA sensitization and challenge, St3gal3+/- and St3gal3 -/- mice have more intense allergic eosinophilic airway inflammation and less sialylated Siglec-F ligands in their airways. One possible explanation for these findings is that levels of sialylated airway ligands for Siglec-F might be diminished in mice with attenuated levels of ST3Gal-III, resulting in a reduction in a natural proapoptotic pathway for controlling airway eosinophilia.