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

Slides:



Advertisements
Similar presentations
A critical role of IL-33 in experimental allergic rhinitis
Advertisements

Anju T. Peters, MD, Atsushi Kato, PhD, Ning Zhang, PhD, David B
Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease  Purvi Mehrotra, PhD, Andrew Hollenbeck,
Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3  Feng Lan, MD, Nan Zhang,
Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge  Mei Ming, PhD, Baozhong Zhao, PhD, Christopher.
Epoxyeicosatrienoic acids are involved in the C70 fullerene derivative–induced control of allergic asthma  Sarah K. Norton, PhD, Dayanjan S. Wijesinghe,
Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3  Feng Lan, MD, Nan Zhang,
The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic.
Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M
Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.
IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells  Samuel J. Wadsworth,
Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois  Bruce K. Tan, MD, MS, Aiko I. Klingler, PhD,
Let-7 microRNA–mediated regulation of IL-13 and allergic airway inflammation  Manish Kumar, MSc, Tanveer Ahmad, MSc, Amit Sharma, PhD, Ulaganathan Mabalirajan,
IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis  Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,
Anju T. Peters, MD, Atsushi Kato, PhD, Ning Zhang, PhD, David B
Extracellular eosinophilic traps in association with Staphylococcus aureus at the site of epithelial barrier defects in patients with severe airway inflammation 
Cigarette smoke extract induces thymic stromal lymphopoietin expression, leading to TH2-type immune responses and airway inflammation  Yuki Nakamura,
Julie M. Caldwell, PhD, Carine Blanchard, PhD, Margaret H
The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter  Jeremy A. Hirota,
Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance  Laura.
Restoration of T-box–containing protein expressed in T cells protects against allergen- induced asthma  Jung Won Park, MD, Hyun Jung Min, MS, Jung Ho Sohn,
Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.
Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation  Si-Yen Liu, PhD, Wei-Zhi Wang,
Chronic rhinosinusitis with polyps and without polyps is associated with increased expression of suppressors of cytokine signaling 1 and 3  Se Jin Park,
Expression of 11β-hydroxysteroid dehydrogenase 1 and 2 in patients with chronic rhinosinusitis and their possible contribution to local glucocorticoid.
Evidence of a role for B cell–activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps  Atsushi Kato, PhD,
The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells  Jane Eddleston, PhD, Jack Herschbach,
Role of TWIK-related potassium channel-1 in chronic rhinosinusitis
Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma  Muhannad Hassan, MD, Taisuke Jo, MD, PhD, Paul-André Risse, PhD,
Volume 87, Issue 2, Pages (February 2015)
Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α  John T. Schroeder, PhD,
Role of p63/p73 in epithelial remodeling and their response to steroid treatment in nasal polyposis  Chun Wei Li, PhD, Li Shi, MD, Ke Ke Zhang, MD, Tian.
Overexpression of sirtuin 6 suppresses allergic airway inflammation through deacetylation of GATA3  Hyun-Young Jang, PhD, Suna Gu, MS, Sang-Myeong Lee,
Increased expression of CC chemokine ligand 18 in patients with chronic rhinosinusitis with nasal polyps  Sarah Peterson, MD, Julie A. Poposki, MS, Deepti.
Programmed cell death ligand 1 alleviates psoriatic inflammation by suppressing IL-17A production from programmed cell death 1–high T cells  Jong Hoon.
A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell–dependent murine model of allergic asthma 
Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms  Wenru Su, MD,
Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis  Mario Noti,
Cross-talk between human mast cells and epithelial cells by IgE-mediated periostin production in eosinophilic nasal polyps  Dae Woo Kim, MD, PhD, Marianna.
Bcl2-like protein 12 plays a critical role in development of airway allergy through inducing aberrant TH2 polarization  Zhi-Qiang Liu, MD, PhD, Ying Feng,
Volume 75, Issue 12, Pages (June 2009)
Antigen-presenting epithelial cells can play a pivotal role in airway allergy  Julia Arebro, MD, Lotta Tengroth, MSc, Ronia Razavi, MSc, Susanna Kumlien.
Inhibition of ABCC4 potentiates combination beta agonist and glucocorticoid responses in human airway epithelial cells  Ryan D. Huff, MSc, Christopher.
Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells  Elizabeth.
David D. Tieu, MD, Anju T. Peters, MD, Roderick T
Nerve growth factor induces type III collagen production in chronic allergic airway inflammation  Ayşe Kılıç, MSc, Sanchaita Sriwal Sonar, PhD, Ali Oender.
Mast cell–derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma  Ara Jo, PhD, Sun H.
Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway  Meiqin Wang, MD, PhD, Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi,
Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome  Simon J. Pelham, MSc, Helen C. Lenthall,
Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis  Deepti R. Nagarkar, PhD, Julie A. Poposki,
Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis  Sudarshan Seshadri,
T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production  Ayako Matsuki, MD, Hiroaki Takatori, MD,
T-bet inhibits innate lymphoid cell–mediated eosinophilic airway inflammation by suppressing IL-9 production  Ayako Matsuki, MD, Hiroaki Takatori, MD,
Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps  Tetsuji Takabayashi, MD, Atsushi Kato, PhD,
Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease  Purvi Mehrotra, PhD, Andrew Hollenbeck,
IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis  Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,
Duy Pham, PhD, Sarita Sehra, PhD, Xin Sun, PhD, Mark H. Kaplan, PhD 
Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma 
The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis  Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,
Defective epithelial barrier in chronic rhinosinusitis: The regulation of tight junctions by IFN-γ and IL-4  Michael B. Soyka, MD, Paulina Wawrzyniak,
IgE induces transcriptional regulation of thymic stromal lymphopoietin in human airway smooth muscle cells  Naresh Singh Redhu, MSc, Ali Saleh, PhD, Hai-Chon.
CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4  Kandace Bonner,
Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency  Douglas.
Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation  Takumi Kiwamoto,
The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice  Martin Kohan, MSc, Andres F. Muro,
Inflammation-mediated upregulation of centrosomal protein 110, a negative modulator of ciliogenesis, in patients with chronic rhinosinusitis  Yinyan Lai,
Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis  Jennifer K. Mulligan, PhD, Whitney Nagel,
Nrf2 activation by sulforaphane restores the age-related decrease of TH1 immunity: Role of dendritic cells  Hyon-Jeen Kim, PhD, Berenice Barajas, BS,
Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation  Takumi Kiwamoto,
CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4  Kandace Bonner,
Presentation transcript:

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