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

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Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation Takumi Kiwamoto, MD, PhD, Mary E. Brummet, MS, Fan Wu, Mary G. Motari, David F. Smith, PhD, Ronald L. Schnaar, PhD, Zhou Zhu, MD, PhD, Bruce S. Bochner, MD Journal of Allergy and Clinical Immunology Volume 133, Issue 1, Pages 240-247.e3 (January 2014) DOI: 10.1016/j.jaci.2013.05.018 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Glycan array screening with Version 4.2 of the Consortium for Functional Glycomics glycan array (http://www.functionalglycomics.org) reveals 2 shared ligands for Siglec-F-Fc (1 μg/mL) and Siglec-8-Fc (200 μg/mL) among 465 glycans tested, namely 6′-su-sLex and 6′-su-sLacNAc. Values represent means ± SDs of replicates from a single assay. Structures are displayed with nomenclature used in the Essentials of Glycobiology textbook, second edition (http://www.ncbi.nlm.nih.gov/books/NBK1908/). Diamonds, N-acetylneuraminic acid (sialic acid); circles, galactose; squares, N-acetylglucosamine; triangles, fucose. B, Chemical structures of the 2 shared ligands, 6′-su-sLex and 6′-su-sLacNAc, that differ only with respect to the presence or absence, respectively, of the fucose residue. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 St3gal3+/− and St3gal3−/− mice demonstrate decreased Siglec-F ligand expression in the lung and airway. A, Constitutive ligand characterization in WT, St3gal3+/−, and St3gal3−/− mouse whole-lung parenchymal extracts with or without sialidase pretreatment probed by means of Western blotting with Siglec-F-Fc and for β-actin as a positive control. For each lane, 150 μg of lung extract protein was loaded. Data are representative of 3 experiments with similar results. B, Western blotting of mouse whole-lung parenchymal extracts in control and OVA-sensitized and challenged mice probed with Siglec-F-Fc or β-actin. Data are representative of 3 experiments with similar results. C, Representative detection and localization of Siglec-F ligand by using Siglec-F-Fc in immunohistochemistry from lung tissues of normal WT, St3gal3+/−, and St3gal3−/− mice in tracheal epithelium (panels a-f) and submucosal tracheal glands (panels g-l). All samples were obtained 24 hours after final challenge with PBS or OVA. Data are representative of 3 experiments with similar results. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Attenuation of St3gal3 is associated with enhanced OVA-induced allergic eosinophilic airway inflammation. A, BALF cytology of each indicated cell type using samples obtained 24 hours after PBS or OVA final challenge from WT, St3gal3+/−, and St3gal3−/− mice (n = 8-12). B, Representative lung tissue sections from WT (panels a and b), St3gal3+/− (panels c and d), and St3gal3−/− (panels e and f) mice obtained 24 hours after PBS (panels a, c, and e) or OVA (panels b, d, and f) final challenge analyzed by using immunohistochemistry after being labeled with anti-MBP mAb. Representative photomicrographs are provided for each group (magnification ×200). C, Peribronchial eosinophils (MBP+ cells) in lung tissue sections (like those in Fig 3, B) were enumerated. Values represent means ± SDs (n = 5-7). For Fig 3, A and C, horizontal bars indicate direct statistical comparisons between OVA-challenged WT, St3gal3+/−, or St3gal3−/− mice. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of attenuation of St3gal3 on OVA-induced serologic markers associated with allergic sensitization. Total IgE (A), OVA-specific IgE (B), OVA-specific IgG1 (C), and OVA-specific IgG2a (D) levels in serum obtained 24 hours after PBS or OVA final challenge (n = 9-13). *P < .05, **P < .01, and ***P < .001 relative to the WT-PBS control mice. Horizontal bars indicate direct statistical comparisons between OVA-challenged WT, St3gal3+/−, or St3gal3−/− mice. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Localization of Siglec-F ligand in OVA-challenged mouse trachea (A) and lung (B). Fig E1, A, Sialidase-sensitive Siglec-F ligands were expressed in airway epithelium and submucosal glands (panels b-g). Fig E1, B, Siglec-F ligands were observed in bronchial epithelium in lung tissue (panels b-d). Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Attenuation of St3gal3 enhances the percentages of eosinophils in OVA-induced allergic eosinophilic airway inflammation (A, n = 8-12) but has no effect on peripheral blood (PB) eosinophil numbers (B, n = 9-14) when examined 24 hours after PBS or OVA final challenge. ∗P < .05 and ∗∗∗P < .001. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Effect of attenuation of St3gal3 on levels of various cytokines and chemokines in BALF. Levels of the indicated mediators (A-L, with median values also shown) were quantified in BALF obtained 24 hours after PBS or OVA final challenge (n = 6-15). *P < .05 and **P < .01 relative to WT-PBS control mice. Horizontal bars above each set of data indicate direct statistical comparisons between OVA-challenged WT, St3gal3+/−, or St3gal3−/− mice. Dashed red lines indicate the level of detection. NS, Not significant. Journal of Allergy and Clinical Immunology 2014 133, 240-247.e3DOI: (10.1016/j.jaci.2013.05.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions