title: Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.
abstract: BACKGROUND
  Mutations in the human filaggrin gene (FLG) are associated with atopic dermatitis (AD) and are presumed to provoke a barrier abnormality. Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris.
  
  
  OBJECTIVE
  We examined here whether FLG deficiency alone suffices to produce a barrier abnormality, the basis for the putative abnormality, and its proinflammatory consequences.
  
  
  METHODS
  By using the flaky-tail mouse, which lacks processed murine filaggrin because of a frameshift mutation in the gene encoding profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality, further localized the defect, identified its subcellular basis, and assessed thresholds to irritant- and hapten-induced dermatitis.
  
  
  RESULTS
  Flaky-tail mice exhibit low-grade inflammation with increased bidirectional, paracellular permeability of water-soluble xenobiotes caused by impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in wild-type mice, flaky-tail mice experience a severe AD-like dermatosis with a further deterioration in barrier function and features of a T(H)2 immunophenotype (increased CRTH levels plus inflammation, increased serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).
  
  
  CONCLUSIONS
  FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.
authors.affiliation: Department of Dermatology, Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, Calif 94121, USA.
authors.forename: Tiffany C
authors.initials: TC
authors.lastname: Scharschmidt
authors.forename: Mao-Qiang
authors.initials: MQ
authors.lastname: Man
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hatano
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Roshan
authors.initials: R
authors.lastname: Gunathilake
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Silva
authors.forename: Theodora M
authors.initials: TM
authors.lastname: Mauro
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.forename: Soyun
authors.initials: S
authors.lastname: Cho
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Anna
authors.initials: A
authors.lastname: Celli
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology*; D000091344:Filaggrin Proteins; D006241:Haptens / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism; D007509:Irritants / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D010081:Oxazolone / Q000494:pharmacology; D012867:Skin / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D002273:Carcinogens; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D006241:Haptens; D007381:Intermediate Filament Proteins; D007509:Irritants; D010081:Oxazolone; D007073:Immunoglobulin E; D013755:Tetradecanoylphorbol Acetate