Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:135

Article

Kiwamoto, Takumi¹  Katoh, Toshihiko²  Evans, Christopher M.³  Janssen, William J.^3,4  Brummet, Mary E.¹  Hudson, Sherry A.¹  Zhu, Zhou¹  Tiemeyer, Michael²  Bochner, Bruce S.¹ 

[1] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA

[2] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA

[3] Univ Colorado, Sch Med, Dept Med, Div Pulm Med, Denver, CO USA

[4] Natl Jewish Hlth, Dept Med, Div Pulm Crit Care & Sleep Med, Denver, CO USA

关键词: Eosinophil;    asthma;    Siglec-F;    mucin;    Muc5b;    Muc4;    apoptosis;    glycan ligands;    epithelium;    glands;    lung;    airway;   

DOI  :  10.1016/j.jaci.2014.10.027

来源: Elsevier

【 摘 要 】

Background: Sialic acid-binding, immunoglobulin-like lectin (Siglec) F is a glycan-binding protein selectively expressed on mouse eosinophils. Its engagement induces apoptosis, suggesting a pathway for ameliorating eosinophilia in the setting of asthma and other eosinophil-associated diseases. Siglec-F recognizes sialylated sulfated glycans in glycan-binding assays, but the identities of endogenous sialoside ligands and their glycoprotein carriers in vivo are unknown. Objectives: To use mouse lung-derived materials to isolate, biochemically identify, and biologically characterize naturally occurring endogenous glycan ligands for Siglec-F. Methods: Lungs from normal and mucin-deficient mice, as well as mouse tracheal epithelial cells, were investigated in vitro and in vivo for the expression of Siglec-F ligands. Western blotting and cytochemistry used Siglec-F-Fc as a probe for directed purification, followed by liquid chromatography-tandem mass spectrometry of recognized glycoproteins. Purified components were tested in mouse eosinophil-binding assays and flow cytometry-based cell death assays. Results: We detected mouse lung glycoproteins that bound to Siglec-F; binding was sialic acid dependent. Proteomic analysis of Siglec-F binding material identified Muc5b and Muc4. Cross-affinity enrichment and histochemical analysis of lungs from mucin-deficient mice assigned and validated the identity of Muc5b as one glycoprotein ligand for Siglec-F. Purified mucin preparations carried sialylated and sulfated glycans, bound to eosinophils and induced their death in vitro. Mice conditionally deficient in Muc5b displayed exaggerated eosinophilic inflammation in response to intratracheal installation of IL-13. Conclusions: These data identify a previously unrecognized endogenous anti-inflammatory property of airway mucins by which their glycans can control lung eosinophilia through engagement of Siglec-F.

【 授权许可】

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