Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation.

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 IgG1 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.

• Authors: Takumi Kiwamoto, Mary E Brummet, Fan Wu, Mary G Motari, David F Smith, Ronald L Schnaar, Zhou Zhu, Bruce S Bochner
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 133 Issue 1 Pg. 240-7.e1-3 (Jan 2014) ISSN: 1097-6825 [Electronic] United States
• PMID: 23830412 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

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

Topics

• Animals
• Antigens, Differentiation, Myelomonocytic (genetics, metabolism)
• Apoptosis (genetics)
• Bronchoalveolar Lavage Fluid (immunology)
• Cytokines (immunology)
• Eosinophils (immunology)
• Immunization
• Immunoglobulin G (blood)
• Lung (immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Ovalbumin (immunology)
• Pneumonia (genetics, immunology)
• Sialic Acid Binding Immunoglobulin-like Lectins
• Sialyltransferases (genetics)
• beta-Galactoside alpha-2,3-Sialyltransferase