Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.
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.
Scharschmidt
Tiffany C
TC
Department of Dermatology, Dermatology Service, Veterans Affairs Medical Center, University of California, San Francisco, Calif 94121, USA.
Man
Mao-Qiang
MQ
Hatano
Yutaka
Y
Crumrine
Debra
D
Gunathilake
Roshan
R
Sundberg
John P
JP
Silva
Kathleen A
KA
Mauro
Theodora M
TM
Hupe
Melanie
M
Cho
Soyun
S
Wu
Yan
Y
Celli
Anna
A
Schmuth
Matthias
M
Feingold
Kenneth R
KR
Elias
Peter M
PM
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
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