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
Robida, Piper A; Puzzovio, Pier Giorgio; Pahima, Hadas et al. (2018) Human eosinophils and mast cells: Birds of a feather flock together. Immunol Rev 282:151-167
O'Sullivan, Jeremy A; Carroll, Daniela J; Cao, Yun et al. (2018) Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e7
O'Sullivan, Jeremy A; Wei, Yadong; Carroll, Daniela J et al. (2018) Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils. J Leukoc Biol 104:11-19
Edgar, Landon J; Kawasaki, Norihito; Nycholat, Corwin M et al. (2018) Targeted Delivery of Antigen to Activated CD169+ Macrophages Induces Bias for Expansion of CD8+ T Cells. Cell Chem Biol :
Khoury, Paneez; Bochner, Bruce S (2018) Consultation for Elevated Blood Eosinophils: Clinical Presentations, High Value Diagnostic Tests, and Treatment Options. J Allergy Clin Immunol Pract 6:1446-1453
Chen, Zi; Bai, Fang-Fang; Han, Lu et al. (2018) Targeting Neutrophils in Severe Asthma via Siglec-9. Int Arch Allergy Immunol 175:5-15
O'Sullivan, Jeremy A; Bochner, Bruce S (2018) Eosinophils and eosinophil-associated diseases: An update. J Allergy Clin Immunol 141:505-517
Bochner, Bruce S (2018) The eosinophil: For better or worse, in sickness and in health. Ann Allergy Asthma Immunol 121:150-155
Gonzalez-Gil, Anabel; Porell, Ryan N; Fernandes, Steve M et al. (2018) Sialylated keratan sulfate proteoglycans are Siglec-8 ligands in human airways. Glycobiology 28:786-801
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83

Showing the most recent 10 out of 78 publications