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

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 1; pp. 240 - 247.e3
• Main Authors: Kiwamoto, Takumi, MD, PhD, Brummet, Mary E., MS, Wu, Fan, Motari, Mary G, Smith, David F., PhD, Schnaar, Ronald L., PhD, Zhu, Zhou, MD, PhD, Bochner, Bruce S., MD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 2014; Elsevier
• Subjects: 6′-sulfated sialyl Lewis X; 6′-sulfated sialyl N-acetyl-D-lactosamine; Allergic diseases; Allergy and Immunology; Animals; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - metabolism; apoptosis; Apoptosis - genetics; asthma; Biological and medical sciences; Bronchoalveolar Lavage Fluid - immunology; Cytokines - immunology; Eosinophils; Eosinophils - immunology; glycan ligands; Immunization; Immunoglobulin G - blood; Immunopathology; lung; Lung - immunology; Lung - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin - immunology; Pneumonia - genetics; Pneumonia - immunology; Respiratory and ent allergic diseases; Sialyltransferases - genetics; Siglec-F; St3gal3; Siglec-8-Fc; 6’-su-sLacNAc; Major basic protein; Siglec-F human IgG 1 Fc chimera; apoptosis; 6′-su-sLe x; St3gal3 gene product α2,3 sialyltransferase; ST3Gal-III; MBP; WT; Ovalbumin; Sialic acid–binding immunoglobulin-like lectin; Siglec; St3gal3; Siglec-F; BALF; Siglec-8 human IgG 1 Fc chimera; asthma; Wild-type; lung; glycan ligands; Siglec-F-Fc; 6′-sulfated sialyl Lewis X; Bronchoalveolar lavage fluid; OVA; 6′-sulfated sialyl N-acetyl-D-lactosamine; Eosinophils; 6′-su-sLex; Immunopathology; Allergy; Lectin; Sialic acid; Ligand; 6'-sulfated sialyl Lewis X; Rodentia; Inflammation; Eosinophil; Respiratory tract; Vertebrata; Mammalia; Mouse; 6ʹ-sulfated sialyl N-acetyl-D-lactosamine; Animal; Apoptosis; 6′-Sulfated sialyl N-acetyl-D-lactosamine; Siglec-8 human IgG Fc chimera; Siglec-F human IgG Fc chimera; 6′-su-sLe(x); 6′-Sulfated sialyl Lewis X
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.05.018

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.