Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 144, Issue 3, Pages 698-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.05.010
Keywords
Asthma; epithelial fucosylation; fucosyltransferase 2; C3a; monocyte-derived dendritic cells
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Funding
- Institute for Global Prominent Research, Chiba University, Japan
- Glaxo Smith Kline, Japan
- Takeda Science Foundation, Japan
- Ministry of Education, Culture, Sports and Technology of the Japanese Government [17K09645]
- Grants-in-Aid for Scientific Research [17K09645] Funding Source: KAKEN
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Background: One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma. Objective: The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma. Methods: We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation. Results: On allergen inhalation, lung epithelial cells were heavily alpha(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13-signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2(-/-)) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)-induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2(-/-) mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor-expressing monocyte-derived dendritic cells in the lung on HDM challenge. Conclusion: Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.
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