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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 240-247.e3 |
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 133 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2014 |
Funding
Disclosure of potential conflict of interest: T. Kiwamoto, F. Wu, M. G. Motari, and Z. Zhu have received grants from the National Institutes of Health (NIH) . D. F. Smith has received a grant from Emory University School of Medicine . R. L. Schnaar has received grants and travel support from the NIH , has received royalties from Oxford University Press and Johns Hopkins , has stock/stock options in Zacharon Pharmaceuticals, and has received travel support from Academia Sinica and the University of Alberta . B. S. Bochner has received a grant from the NIH , has consultant arrangements with Allakos, has patents through Johns Hopkins University regarding Siglec-8 and its ligand, receives royalties from Johns Hopkins University , and has an equity position in Allakos. M. E. Brummet declares that she has no relevant conflicts of interest. Supported by grants AI72265 and HL107151 from the National Institutes of Health .
Keywords
- 6′-sulfated sialyl Lewis X
- 6′-sulfated sialyl N-acetyl-D-lactosamine
- Eosinophils
- Siglec-F
- St3gal3
- apoptosis
- asthma
- glycan ligands
- lung
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology