title: Loss of sirtuin 1 (SIRT1) disrupts skin barrier integrity and sensitizes mice to epicutaneous allergen challenge.
abstract: BACKGROUND
  Skin barrier integrity requires a highly coordinated molecular system involving the structural protein filaggrin (FLG). Mutational loss of the skin barrier protein FLG predisposes subjects to the development of atopic dermatitis (AD).
  
  
  OBJECTIVE
  We sought to determine the role of sirtuin 1 (SIRT1) in skin barrier function, FLG expression, and development of AD.
  
  
  METHODS
  Skin histology of mice with skin-specific SIRT1 deletion and wild-type control animals was examined by using hematoxylin and eosin staining. Protein and mRNA abundance was analyzed by means of immunoblotting, immunohistochemistry, immunofluorescence, and RT-PCR. Serum antibody levels were assessed by means of ELISA.
  
  
  RESULTS
  Here we show that FLG is regulated by the protein deacetylase SIRT1 and that SIRT1 is critical for skin barrier integrity. Epidermis-specific SIRT1 ablation causes AD-like skin lesions in mice, and mice with epidermal SIRT1 deletion are sensitive to percutaneous challenge by the protein allergen ovalbumin. In normal human keratinocytes and mouse skin SIRT1 knockdown or genetic deletion downregulates FLG, and regulation of FLG expression by SIRT1 requires the deacetylase activity of SIRT1. SIRT1 also promotes activation of the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor ligand restores FLG expression in SIRT1-inhibited cells. Compared with normal human skin, SIRT1 is downregulated in both AD and non-AD lesions.
  
  
  CONCLUSIONS
  Our findings demonstrate a critical role of SIRT1 in skin barrier maintenance, open up new opportunities to use SIRT1 as a pharmacologic target, and might facilitate the development of mechanism-based agents for AD prevention and therapy.
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Mei
authors.initials: M
authors.lastname: Ming
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Baozhong
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Shea
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Palak
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Medicine, Section of Pulmonary/Critical Care, University of Chicago, Chicago, Ill.
authors.forename: Steven R
authors.initials: SR
authors.lastname: White
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Sims
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Ill. Electronic address: yyhe@medicine.bsd.uchicago.edu.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: He
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D000091344:Filaggrin Proteins; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000485:Allergens; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D018336:Receptors, Aryl Hydrocarbon; D007073:Immunoglobulin E; D051057:Proto-Oncogene Proteins c-akt; D056564:Sirtuin 1
keywords: Sirtuin 1 (SIRT1); filaggrin; skin barrier