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Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens

Cited 190 time in Web of Science Cited 214 time in Scopus
Authors

Scharschmidt, Tiffany C.; Man, Mao-Qiang; Hatano, Yutaka; Crumrine, Debra; Sundberg, John P.; Mauro, Theodora M.; Cho, Soyun; Celli, Anna; Feingold, Kenneth R.; Elias, Peter M.; Schmuth, Matthias; Wu, Yan; Hupe, Melanie; Silva, Kathleen A.; Gunathilake, Roshan

Issue Date
2009-09
Publisher
MOSBY-ELSEVIER
Citation
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY; Vol.124(3); 496-506
Keywords
Atopic dermatitiscontact dermatitisflaky-tail mouselamellar bodyfilaggrinbarrier function
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.
ISSN
0091-6749
Language
English
URI
https://hdl.handle.net/10371/78271
DOI
https://doi.org/10.1016/j.jaci.2009.06.046
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College of Medicine/School of Medicine (의과대학/대학원)Dermatology (피부과학전공)Journal Papers (저널논문_피부과학전공)
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