Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition

Background Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase,...

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Published in:Journal of allergy and clinical immunology 2016-01, Vol.137 (1), p.87-98.e7
Main Authors: Lee, Mingyu, BSc, Kim, Dae Woo, MD, PhD, Yoon, Haejin, PhD, So, Daeho, BSc, Khalmuratova, Roza, MD, PhD, Rhee, Chae-Seo, MD, PhD, Park, Jong-Wan, MD, PhD, Shin, Hyun-Woo, MD, PhD
Format: Article
Language:English
Subjects:
Adult
Aged
Allergy and Immunology
animal model
Animals
Antibiotics
Cell Line
DNA - genetics
Endoscopy
Epithelial Cells - immunology
Epithelial-Mesenchymal Transition
epithelial-to-mesenchymal transition
Female
Humans
Hypoxia
hypoxia-inducible factor 1
Hypoxia-Inducible Factor 1, alpha Subunit - immunology
Immunoglobulin E - blood
Immunoglobulin E - immunology
Immunoglobulins
Inflammation
Laboratories
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Nasal Mucosa - cytology
Nasal polyposis
Nasal Polyps - immunology
Ovalbumin - immunology
Plasmids
Proteins
RNA, Small Interfering
Sinuses
sirtuin 1
Sirtuin 1 - genetics
Sirtuin 1 - immunology
Surgery
Vascular endothelial growth factor
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Summary:Background Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1–induced EMT. Objective We sought to determine the role of SIRT1 in patients with nasal polyposis. Methods The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxic markers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs. Results SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not. Conclusion SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1–induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2015.07.026