Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge Mei Ming, PhD, Baozhong Zhao, PhD, Christopher.

Slides:

Advertisements

Similar presentations

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

Advertisements

Upregulation of miR-18a-5p contributes to epidermal necrolysis in severe drug eruptions Asako Ichihara, MD, PhD, Zhongzhi Wang, PhD, Masatoshi Jinnin,

Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated.

Weiguo Chen, PhD, Umasundari Sivaprasad, PhD, Aaron M

Let-7 microRNA–mediated regulation of IL-13 and allergic airway inflammation Manish Kumar, MSc, Tanveer Ahmad, MSc, Amit Sharma, PhD, Ulaganathan Mabalirajan,

Thymic stromal lymphopoietin downregulates filaggrin expression by signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated.

Role of fibroblasts in the pathogenesis of atopic dermatitis

Umasundari Sivaprasad, PhD, David J. Askew, PhD, Mark B

SERPINB3/B4 Contributes to Early Inflammation and Barrier Dysfunction in an Experimental Murine Model of Atopic Dermatitis Umasundari Sivaprasad, Kayla.

A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells Motohiko Suzuki, MD, PhD, Xiufen Zheng, PhD, Xusheng Zhang, MD, PhD,

Cigarette smoke extract induces thymic stromal lymphopoietin expression, leading to TH2-type immune responses and airway inflammation Yuki Nakamura,

Activation of protease-activated receptor 2 leads to impairment of keratinocyte tight junction integrity Peter Nadeau, BS, Mason Henehan, BS, Anna De.

IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in atopic dermatitis Norbert Meyer, MD, Maya Zimmermann, PhD,

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

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,

Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival Jyoti Balhara, MSc, Lianyu Shan,

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

IL-33 induces innate lymphoid cell–mediated airway inflammation by activating mammalian target of rapamycin Robert J. Salmond, PhD, Ananda S. Mirchandani,

Whole-exome sequencing in patients with ichthyosis reveals modifiers associated with increased IgE levels and allergic sensitizations Dimitra Kiritsi,

CtBP1 Overexpression in Keratinocytes Perturbs Skin Homeostasis

Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis Hiroyuki Murota, MD, PhD, Mayuko Izumi, MSc,

Peroxisome proliferator-activated receptor α regulates skin inflammation and humoral response in atopic dermatitis Delphine Staumont-Sallé, MD, Georges.

Chang Xiao, MD, PhD, Jocelyn M

Sarita Sehra, Ana P. M. Serezani, Jesus A. Ocaña, Jeffrey B

Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia Asuka Honjo, MD, Nobuhiro Nakano, PhD, Susumu.

Circadian clock gene Period2 regulates a time-of-day–dependent variation in cutaneous anaphylactic reaction Yuki Nakamura, Daisuke Harama, Naomi Shimokawa,

Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang,

Heme oxygenase 1 attenuates the development of atopic dermatitis–like lesions in mice: Implications for human disease Mio Kirino, MD, Yohei Kirino, MD,

Toluene downregulates filaggrin expression via the extracellular signal-regulated kinase and signal transducer and activator of transcription–dependent.

Christina A. Young, Richard L

Overexpression of sirtuin 6 suppresses allergic airway inflammation through deacetylation of GATA3 Hyun-Young Jang, PhD, Suna Gu, MS, Sang-Myeong Lee,

Critical role of IgE-dependent mast cell activation in a murine model of allergic conjunctivitis Ken Fukuda, MD, PhD, Masaharu Ohbayashi, PhD, Kei Morohoshi,

IL-36γ Induced by the TLR3-SLUG-VDR Axis Promotes Wound Healing via REG3A Ziwei Jiang, Yuanqi Liu, Changwei Li, Leilei Chang, Wang Wang, Zhenhua Wang,

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis Mario Noti,

Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis Bodi.

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,

MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity Jing Jing Li, MS, Hock L. Tay, PhD, Steven.

Role of the Notch Ligand Delta1 in Embryonic and Adult Mouse Epidermis

Jethe O. F. Nunes, PhD, Juliana de Souza Apostolico, MSc, David A. G

Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide Weishan Huang, PhD, J. Luis Morales,

The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling Wataru.

Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β– mediated airway remodeling in asthma Christian Karagiannidis, MD, Gabriele.

Antiviral activity of human β-defensin 3 against vaccinia virus

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,

Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization Haoli Jin, MD, PhD, Lalit Kumar, PhD, Clinton Mathias, PhD, David Zurakowski,

Thymic stromal lymphopoietin–activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis Wen Hao Wu, PhD,

Sabine Leisten, MSc, Michiko K

Volume 23, Issue 7, Pages (July 2015)

A novel allergen-specific therapy with CD40-silenced B cells and dendritic cells Motohiko Suzuki, MD, PhD, Makoto Yokota, MD, PhD, Yoshihisa Nakamura,

Receptor-interacting protein kinase 3 controls keratinocyte activation in a necroptosis- independent manner and promotes psoriatic dermatitis in mice

Yuko Oda, Lizhi Hu, Vadim Bul, Hashem Elalieh, Janardan K

Localization of Serine Racemase and Its Role in the Skin

Orally administered TGF-β is biologically active in the intestinal mucosa and enhances oral tolerance Takashi Ando, MD, PhD, Kyosuke Hatsushika, MD,

Allergic skin sensitization promotes eosinophilic esophagitis through the IL-33–basophil axis in mice Nicholas Venturelli, BS, Willem S. Lexmond, MD,

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung Sun-Young Oh, PhD,

Nrf2 Promotes Keratinocyte Proliferation in Psoriasis through Up-Regulation of Keratin 6, Keratin 16, and Keratin 17 Luting Yang, Xueli Fan, Tingting.

Oral administration of a synthetic agonist of Toll-like receptor 9 potently modulates peanut-induced allergy in mice Fu-Gang Zhu, PhD, Ekambar R. Kandimalla,

Sarita Sehra, Ana P. M. Serezani, Jesus A. Ocaña, Jeffrey B

Langerhans cells are critical in epicutaneous sensitization with protein antigen via thymic stromal lymphopoietin receptor signaling Saeko Nakajima,

IL-17A Upregulates Keratin 17 Expression in Keratinocytes through STAT1- and STAT3- Dependent Mechanisms Xiaowei Shi, Liang Jin, Erle Dang, Ting Chang,

The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling Wataru.

TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis Shin Morizane, MD, PhD, Kenshi Yamasaki, MD, PhD, Ai Kajita,

Prostaglandin E receptor subtype EP3 in conjunctival epithelium regulates late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD,

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,

Jenny Seltmann, PhD, Lennart M

Prostaglandin E2–EP3 signaling suppresses skin inflammation in murine contact hypersensitivity Tetsuya Honda, MD, PhD, Toshiyuki Matsuoka, MD, PhD, Mayumi.

Claudin 5 in a murine model of allergic asthma: Its implication and response to steroid treatment Kuk-Young Moon, MS, Pureun-Haneul Lee, BS, Byeong-Gon.

Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis patients is independent of FLG gene mutations Laurence Pellerin, PhD,

Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression Atsushi Otsuka, MD, PhD, Hiromi Doi, MS, Gyohei.

Presentation transcript:

Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge Mei Ming, PhD, Baozhong Zhao, PhD, Christopher R. Shea, MD, Palak Shah, MB, Lei Qiang, PhD, Steven R. White, MD, Diane M. Sims, BS, Yu-Ying He, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 4, Pages 936-945.e4 (April 2015) DOI: 10.1016/j.jaci.2014.09.035 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Development of AD-like skin lesions in mice with epidermal SIRT1 deletion (cKO). A, Gross phenotype of 51- to 64-week-old SIRT1 cKO mice. B, Percentage of skin lesion–free mice among SIRT1 WT, cHet, and cKO mice (n = 15). C, Mouse serum IgE levels in SIRT1 WT, cHet, and cKO mice at 18 months of age. D, Representative photomicrographs of HE skin sections from 6-month-old SIRT1 WT, cHet, and cKO mice. Scale bar = 50 μm. E, Numbers of eosinophils detected per high-power field (HPF; ×400 magnification). F, Toluidine blue staining of mast cells in skin of SIRT1 WT, cHet, and cKO mice at 6 months of age. Scale bar = 200 μm. G, Scatter chart for numbers of mast cells per low-power field (LPF; ×100 magnification) in SIRT1 WT, cHet, and cKO mouse skin (n = 3). H, TEWL in 18-month-old SIRT1 WT, cHet, and cKO mice. For Fig 1, C, data are shown as means ± SEs (n = 3). *P < .05, t test, compared with the WT group. For Fig 1, E, G, and H, data are shown as means ± SDs (n = 3). *P < .05, t test, compared with the WT group. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Reduced FLG expression in keratinocytes and mouse skin with SIRT1 loss. A, FLG mRNA levels in undifferentiated NHEKs transfected with NC or siRNA targeting SIRT1 (siSIRT1). Data are shown as means ± SEs from 3 independent experiments. *P < .05, t test, compared with the NC group. B, FLG protein levels in NHEKs transfected with NC or siSIRT1 as in Fig 2, A. C, FLG mRNA levels in 6-month-old SIRT1 WT and cKO mouse skin. D, proFLG and filaggrin monomer (FLG) protein levels in skin from 6-month-old SIRT1 WT and cKO mouse skin. E, Immunohistochemical staining of FLG, K10, and loricrin in skin of 6-month-old WT and SIRT1 cKO mice. Scale bar = 50 μm. F and G, Electron microscopic analysis of WT (Fig 2, F) and SIRT1 cKO (Fig 2, G) epidermis from 6-week-old mice. Red arrows indicate F-granules (F), and blue arrows indicate L-granules (L). Scale bar = 2 μm. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Response to OVA in WT and SIRT1 cKO mice. A, Schematic for OVA treatment. B, Histology of mouse skin after PBS and OVA treatment as in Fig 3, A. Scale bar = 50 μm. C, ELISA of serum IgE levels in SIRT1 WT and cKO mice after PBS and OVA treatment. D, TEWL in SIRT1 WT and cKO mice after PBS and OVA treatment. For all graphs, data are shown as means ± SEs (n = 4). *P < .05, t test, compared with WT group. The mice were 6 to 8 weeks old. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Role of SIRT1 deacetylase activity in its regulation of FLG. A, Immunoblot analysis of proFLG, SIRT1, acetylated p53 (Ac-p53), p53, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein levels in NHEKs transfected with SIRT1 vector (Vec), WT, or inactive mutant (Mut) SIRT1 plasmids. B, Immunoblot analysis of proFLG, SIRT1, Ac-p53, p53, and GAPDH protein levels in 293T cells transfected with Vec, WT, or Mut SIRT1 plasmids. C, FLG mRNA levels in 293T cells transfected with Vec, WT, or Mut SIRT1 plasmids. Data are shown as means ± SEs from 3 independent experiments. *P < .05, t test, compared with the vector group. D, Immunoblot analysis of proFLG, SIRT1, p53, p21, and GAPDH in NHEKs transfected with NC or siRNA targeting p53 (sip53). Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Role of AhR in SIRT1 regulation of FLG. A, Gene array analysis of mRNA levels of CYP1B1 and AhR in NHEKs transfected with NC or siSIRT1. B, Real-time PCR analysis of CYP1B1 mRNA expression in NHEKs transfected with NC or siSIRT1. C, Real-time PCR analysis of CYP1B1 mRNA expression in SIRT1 WT and cKO mouse skin (n = 3). D, Luciferase reporter assay of AhR reporter activity (XRE-luc) in SIRT1 WT and KO MEF cells. E, Immunofluorescence analysis of SIRT1 and CYP1B1 in NHEKs transfected with NC or siSIRT1. 4′-6-Diamidino-2-phenylindole dihydrochloride (DAPI) staining (blue) was used as a nuclear counterstain. Scale bar = 50 μm. F, Immunoblot analysis of FLG, SIRT1, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein levels in NHEKs transfected with NC or siSIRT1 and then treated with BaP (10 μmol/L) for 48 hours. G, Real-time PCR analysis of FLG mRNA levels in NHEKs transfected with NC or siSIRT1 and treated with BaP (10 μmol/L) for 48 hours. H, Real-time PCR analysis of CYP1B1 mRNA levels in NHEKs transfected with NC or siSIRT1 and treated with BaP (10 μmol/L) for 48 hours. I, Immunoblot analysis of filaggrin monomer (FLG) and GAPDH protein levels in SIRT1 cKO mice treated with OVA for 6 weeks, followed by treatment with BaP for 3 or 7 days. J, Representative pictures of hematoxylin and eosin staining for SIRT1 cKO mice treated with OVA for 6 weeks, followed by treatment with BaP for 3 or 7 days. K, Serum IgE levels in SIRT1 cKO mice treated with OVA for 6 weeks, followed by treatment with BaP for 7 days. Scale bar = 50 μm. For all graphs, data are shown as means ± SEs from 3 independent experiments. *P < .05, t test, compared with the control (NC or WT) group for Fig 5, A-D, or the vehicle (Veh) group in Fig 5, G-H. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Role of AKT in AhR regulation of FLG. A, Immunoblot analysis of FLG, CYP1B1, phosphorylated AKT (p-AKT), AKT, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in NHEKs treated with BaP (10 μmol/L) for 48 hours. B, Immunoblot analysis of FLG, p-AKT, AKT, CYP1B1, and GAPDH in NHEKs transfected with siRNA targeting AKT1 (siAKT1) or NC and then treated with vehicle or BaP (10 μmol/L). C, Schematic for the role of SIRT1 in regulating skin barrier function. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 SIRT1 protein levels in human normal, AD, and non-AD skin. A, Alkaline phosphatase–anti-alkaline phosphatase red staining for SIRT1 protein levels in human normal, AD, and non-AD skin. Scale bar = 100 μm. B, Percentage (in stacked column format) for each score of SIRT1 expression. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 SIRT1 protein level and activity in skin from SIRT1 WT, cHet, and cKO mice. A and B, Immunoblot analysis of SIRT1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in skin (Fig E1, A) and liver (Fig E1, B) from WT, cHet, and cKO mice at 4 to 6 weeks of age. The upper band in the SIRT1 blot in Fig E1, A, shows the WT SIRT1 protein (SIRT1), whereas the lower band shows the nonfunctional truncated protein results from the excision of the conserved Sir2 motif of the SIRT1 catalytic domain (ΔSIRT1). C, Fluorometric assay of SIRT1 activity in skin from WT, cHet, and cKO mice (n = 3) at 4 to 6 weeks of age. From Ming et al.23 Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of SIRT1 knockdown on mRNA levels of the epidermal differentiation genes FLG, involucrin, keratin 14, keratin 5, desmoglein 1, desmoglein 2, desmoglein 3, KLK5, KLK7, KLK8, KLK10, KLK11, KLK12, KLK13, matriptase, and SPINK5. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Role of AKT in AhR regulation of FLG. A, Immunoblot analysis of FLG, CYP1B1, phosphorylated AKT (p-AKT), AKT, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in HaCaT cells treated with BaP (10 μmol/L) for 48 hours. B, Immunoblot analysis of FLG, p-AKT, AKT, CYP1B1, and GAPDH in HaCaT cells treated with vehicle, BaP (10 μmol/L), LY294002 (LY; 10 μmol/L), or the combination of BaP and LY294002. C, Immunoblot analysis of FLG, p-AKT, AKT, CYP1B1, and GAPDH in HaCaT cells transfected with siRNA targeting AKT1 (siAKT1) or NC. Journal of Allergy and Clinical Immunology 2015 135, 936-945.e4DOI: (10.1016/j.jaci.2014.09.035) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions