Aiko Saku1, Koichi Hirose2, Takashi Ito1, Arifumi Iwata1, Takashi Sato3, Hiroyuki Kaji3, Tomohiro Tamachi1, Akira Suto1, Yoshiyuki Goto4, Steven E Domino5, Hisashi Narimatsu3, Hiroshi Kiyono6, Hiroshi Nakajima7. 1. Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. 2. Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Rheumatology, School of Medicine, International University of Health and Welfare, Chiba, Japan. Electronic address: hirose-kh@faculty.chiba-u.jp. 3. Glycoscience and Glycotechnology Research Group, Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan. 4. Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan; International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 5. Department of Obstetrics and Gynecology, Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, Mich. 6. International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 7. Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: nakajimh@faculty.chiba-u.jp.
Abstract
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 α(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.
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 α(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.
Authors: Peter W West; Rajia Bahri; Karen M Garcia-Rodriguez; Georgia Sweetland; Georgia Wileman; Rajesh Shah; Angeles Montero; Laura Rapley; Silvia Bulfone-Paus Journal: Front Immunol Date: 2021-02-01 Impact factor: 7.561