Asthma and chronic obstructive pulmonary disease (COPD) involve accumulation and activation of inflammatory cells in the lung. Inflammation in asthma is marked by the influx of eosinophils, mast cells, and CD4+ T-cells whereas COPD is marked by the influx of neutrophils, macrophages and CD8+ T-cells. Members of the Siglec family of glycan binding proteins (sialic acid-binding immunoglobulin-like lectins) are expressed selectively on subsets of inflammatory cells: Siglec-8 on allergic inflammatory cells (eosinophils, mast cells and basophils) and Siglec-9 on monocytes, neutrophils, and some T-cells. Both Siglec-8 and Siglec-9 suppress inflammation. Crosslinking siglecs on inflammatory cells inhibits release of proinflammatory mediators, enhances release of anti-inflammatory mediators, or induces apoptosis/death, depending on the inflammatory cell type. HYPOTHESIS: Glycoconjugate ligands (siglec counter-receptors) in the lung, consisting of endogenous glycoproteins and/or glycolipids, engage Siglec-8 on incoming allergic inflammatory cells and Siglec 9 on COPD inflammatory cells as a feedback mechanism to limit ongoing inflammatory responses.
AIMS : This project will isolate, identify and characterize the human lung counter- receptors for Siglec-8 and Siglec-9. Glycoconjugates (glycoproteins and/or glycolipids) will be extracted from human lung and the major siglec-binding entities will be isolated by conventional, lectin, and Siglec affinity chromatography. The resulting siglec-interacting molecules will be analyzed by mass spectrometry in collaboration with Project 4 of this program. The expression of counter-receptors will be characterized on cultured human lung epithelial and/or endothelial cells and the enzymes responsible for their biosynthesis will be determined by RNAi knockdown. Siglec counter-receptor expression will be compared on normal and diseased human nasal epithelium. The properties of counter-receptors on mouse lung epithelium will be compared with those from human lung. Knowledge of the endogenous human lung counter-receptors for Siglec-8 and Siglec-9 may provide insights useful in understanding the progression of lung inflammatory diseases and may provide improved lead structures for anti-inflammatory therapeutics.

Public Health Relevance

Asthma and COPD, lung diseases that cause extensive illness and death, involve infiltration of damaging inflammatory cells. Normally, sugar molecules in the lung engage complementary molecules on inflammatory cells, signaling them to halt and limiting tissue damage. This project will define those anti-inflammatory sugar molecules in an effort to better understand lung inflammatory diseases and to find new ways to treat them.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
O'Sullivan, Jeremy A; Bochner, Bruce S (2017) Eosinophils and eosinophil-associated diseases: An update. J Allergy Clin Immunol :
Yu, Huifeng; Gonzalez-Gil, Anabel; Wei, Yadong et al. (2017) Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties. Glycobiology 27:657-668
O'Sullivan, Jeremy A; Carroll, Daniela J; Cao, Yun et al. (2017) Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol :
Carroll, Daniela J; O'Sullivan, Jeremy A; Nix, David B et al. (2017) Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating ?2-integrin-dependent function in human eosinophils. J Allergy Clin Immunol :
Guo, Hongbo; de Vries, Erik; McBride, Ryan et al. (2017) Highly Pathogenic Influenza A(H5Nx) Viruses with Altered H5 Receptor-Binding Specificity. Emerg Infect Dis 23:220-231
Lou, Hongfei; Lu, Jingning; Choi, Eun Byul et al. (2017) Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. J Immunol 198:2543-2555
Peng, Wenjie; Paulson, James C (2017) CD22 Ligands on a Natural N-Glycan Scaffold Efficiently Deliver Toxins to B-Lymphoma Cells. J Am Chem Soc 139:12450-12458
Schnaar, Ronald L; Lee, Yuan C (2017) Discoveries of the structures of sialic acid and CMP-sialic acid (1957-1960): A letter from Saul Roseman. Glycobiology :
Wu, Nicholas C; Xie, Jia; Zheng, Tianqing et al. (2017) Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin. Cell Host Microbe 21:742-753.e8
Schleimer, Robert P; Schnaar, Ronald L; Bochner, Bruce S (2016) Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression. Curr Opin Allergy Clin Immunol 16:24-30

Showing the most recent 10 out of 65 publications