Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition Mingyu Lee, BSc, Dae Woo Kim, MD, PhD, Haejin Yoon, PhD,

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Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition Mingyu Lee, BSc, Dae Woo Kim, MD, PhD, Haejin Yoon, PhD, Daeho So, BSc, Roza Khalmuratova, MD, PhD, Chae-Seo Rhee, MD, PhD, Jong-Wan Park, MD, PhD, Hyun-Woo Shin, MD, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 87-98.e7 (January 2016) DOI: 10.1016/j.jaci.2015.07.026 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Polyp burden is reduced in SIRT1 transgenic (TG) mice. A, Protocol for the murine NP model. WT and SIRT1 transgenic mice were treated with OVA and SEB. i.p., Intraperitoneal; i.n., intranasal. B, Photographs of representative sinonasal spaces and polypoid lesions stained with hematoxylin and eosin. The criteria for NPs are described in the Methods section, and dotted circles indicate polypoid lesions. C and D, Numbers of epithelial disruptions and polyps were expressed as the total number per coronal section. *P < .05, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Reciprocal expression of SIRT1 and HIF-1α in patients with CRSwNP or CRSsNP. A, Control UP mucosa from patients without nasal disease, UPs from patients with CRSsNP, and both UP and NP tissues from patients with CRSwNP were immunostained with SIRT1, HIF-1α, and E-cadherin (E-Cad) antibodies. Scale bars = 100 μm. B-D, Comparison of nuclear HIF-1α, SIRT1, and E-cadherin expression in control UPs, UPs from patients with CRSsNP, UPs from patients with CRSwNP, and NPs. Detailed criteria for scoring are described in the Methods section in this article's Online Repository. *P < .05 and **P < .01, Mann-Whitney U test. E, Relationship between nuclear SIRT1 and E-cadherin expression. The Pearson correlation test was used, and R2 represents the coefficient of determination. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of an SIRT1 activator or inhibitor on polyp formation in mice. A, Protocol for the murine NP model. i.p., Intraperitoneal; i.n., intranasal. B, Representative photographs and numbers of polypoid lesions stained with hematoxylin and eosin. NP criteria are described in the Methods section. C and D, Representative photographs and numbers of goblet cells stained with Alcian blue. Fig 3, D, shows OVA-specific IgE levels in mouse serum. *P < .05, Mann-Whitney U test. Scale bar = 50 μm. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 SIRT1 suppresses hypoxia-induced EMT by deacetylating HIF-1α. A, RPMI 2650 cells were transfected with 1 μg of pcDNA or SIRT1 plasmid and incubated under normoxic or hypoxic conditions for 72 hours. EMT markers were immunoblotted. The intensity values of bands were normalized by α-tubulin expression. B and C, RPMI 2650 and A549 cells were treated with resveratrol or vehicle and incubated under normoxic or hypoxic conditions for 72 hours. EMT markers were immunoblotted, and phase-contrast images of hNECs were acquired. Scale bar = 100 μm. D and E, RPMI 2650 cells were treated with resveratrol or vehicle in the HIF-1α–overexpressed or hypoxic conditions (24 hours). Whole-cell lysates and immunoprecipitated proteins were immunoblotted with the indicated antibodies. H, Hypoxic; N, normoxic. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Tissue-specific knockdown of SIRT1 restores polyp formation in SIRT1 transgenic (TG) mice. A, Protocol for the murine NP model. WT and SIRT1 transgenic mice were treated with OVA, SEB, and sh-tGFP or sh-SIRT1 lentiviral vectors. i.p., Intraperitoneal; i.n., intranasal. B, Photographs of representative polypoid lesions stained with hematoxylin and eosin in the indicated groups. C, Photographs of representative immunohistochemical staining against SIRT1. D and E, Numbers of epithelial disruptions and polypoid lesions were compared. *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Increased expression of SIRT1 in nasal epithelial cells treated with mucosal extracts from patients with CRSsNP but not those with CRSwNP. A, SIRT1 expression in RPMI 2650 cells treated with mucosal extracts from control UPs without nasal pathology, UPs of patients with CRS, or NP tissues from patients with CRSwNP. The intensity values of bands were normalized by β-tubulin expression. B and C, hNECs were incubated under normoxic or hypoxic conditions with mucosal extracts from UPs, patients with CRS, or NPs. hNEC phase-contrast images were acquired. Scale bar = 100 μm. D, Epo-luciferase and Epo-mutant luciferase activities with mucosal extracts (20 μg/mL) from UPs, patients with CRS, or NPs as above. *P < .05 and **P < .01, Mann-Whitney U test. H, Hypoxic; N, normoxic. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Schematic illustration of the role of SIRT1 in patients with CRSwNP. In healthy mucosa (A), there is less proinflammatory burden, so SIRT1 expression is very weak. With the subclinical inflammation in sinonasal mucosa (B), SIRT1 could be expressed and compensate the inflammation. Under the persistent or severe inflammation as like CRS (C), SIRT1 could be induced more but may not fully compensate the proinflammatory drives. Thus, the loss of SIRT1 could lead the substantial inflammatory surge and finally nasal polyp formation (D). Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Establishment of the SIRT1 transgenic mouse. A, Structure of the Myc/His-tagged SIRT1 expression vector introduced into transgenic mice. Gene expression was driven under the control of a cytomegalovirus (CMV) promoter. B, The presence of the SIRT1 vector in transgenic mouse was verified by using PCR. C, Expression of endogenous SIRT1 (Endo) and transgenic Myc/His-tagged SIRT1 (transgenic [Tg]) in WT and SIRT1 transgenic mice. Tissue homogenates were prepared from the brain, liver, kidney, and heart and analyzed by means of Western blotting with anti-His and anti-SIRT1 antibodies. D, Paraffin sections of hearts (top panel) and kidneys (bottom panel) from WT and Sirt1 transgenic mice were subjected to immunohistochemical analyses with anti-SIRT1 antibody. Scale bar = 100 μm. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of different inflammatory cytokines on SIRT1 and HIF-1α expression in nasal epithelial cells. RPMI 2650 cells were cultured under normoxic or hypoxic conditions for 12 hours with the indicated cytokines: A, IL-5; B, IFN-γ; C, and IL-17A. Cell lysates were prepared for immunoblotting with the indicated antibodies. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 The effect of resveratrol on HIF-1α–induced EMT. A, HIF-1α was induced by the transfection of HIF-1α plasmid in RPMI2650 cells, and EMT-related markers were traced after resveratrol treatment. B, IFN-γ was treated to RPMI 2650 cells and the effects of resveratrol on EMT-related markers were investigated. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Effect of SIRT1 on HIF-1α deacetylation. A, RPMI 2650 cells were transfected with pcDNA or SIRT1 plasmids, followed by 24 hours of normoxic or hypoxic incubation. Whole cell lysates and immunoprecipitated proteins were immunoblotted with the indicated antibodies. B, RPMI 2650 cells were transfected with HIF-1α and SIRT1 plasmids, followed by 24 hours of normoxic incubation. Whole cell lysates were treated as mentioned above equally. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Comparison of SIRT1, HIF-1α, and E-cadherin (E-Cad) expression between ENPs and NENPs of patients with CRS. NP tissues from patients with CRSwNP were immunostained with SIRT1 (A), HIF-1α (B), and E-cadherin (E-Cad; C) antibodies. Comparison of nuclear HIF-1α, SIRT1, and E-cadherin expression in ENPs and NENPs of patients with CRS. E-cadherin expression was examined with an HPF (×400 magnification) and scored from 0 to +3. The final score of each sample is presented as the average of scores from 3 HPFs. The detailed criteria for scoring are described in the Methods section. n.s., Not significant as determined by using the Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2016 137, 87-98.e7DOI: (10.1016/j.jaci.2015.07.026) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions