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: Tiffany C Scharschmidt, Mao-Qiang Man, Yutaka Hatano, Debra Crumrine, Roshan Gunathilake, John P Sundberg, Kathleen A Silva, Theodora M Mauro, Melanie Hupe, Soyun Cho, Yan Wu, Anna Celli, Matthias Schmuth, Kenneth R Feingold, Peter M Elias
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 124 Issue 3 Pg. 496-506, 506.e1-6 (Sep 2009) ISSN: 1097-6825 [Electronic] United States
• PMID: 19733297 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Carcinogens
• FLG protein, human
• Filaggrin Proteins
• Haptens
• Intermediate Filament Proteins
• Irritants
• Oxazolone
• Immunoglobulin E
• Tetradecanoylphorbol Acetate

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Carcinogens (pharmacology)
• Dermatitis, Atopic (genetics, immunology)
• Filaggrin Proteins
• Haptens (immunology)
• Immunoglobulin E (blood)
• Intermediate Filament Proteins (genetics, metabolism)
• Irritants (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Microscopy, Electron, Transmission
• Oxazolone (pharmacology)
• Skin (immunology)
• Tetradecanoylphorbol Acetate (pharmacology)