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

Abstract

Background Mutations in filaggrin (FLG) are associated with atopic dermatitis (AD), and are presumed to provoke a barrier abnormality. Yet, additional acquired stressors may be necessary, since the same mutations can result in a non-inflammatory 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 pro-inflammatory consequences. Methods Using the flaky-tail (ft/ft) mouse, which lacks processed flg due to a frame-shift mutation in 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 due to 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 +/+ mice, ft/ft mice develop a severe AD-like dermatosis, with a further deterioration in barrier function and features of a th2 immunophenotype (increased CRTH + inflammation, elevated 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.

Flaky Tail Mouse as a Novel Animal Model of Atopic Dermatitis: Possible Roles of Filaggrin in the Development of Atopic Dermatitis

“…Mice of the Flg ft genotype express an abnormal profilaggrin polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. Therefore, filaggrin is absent from the cornified layers in the epidermis of the Flg ft mouse (Fallon, et al, 2009, Presland, et al, 2000, Scharschmidt, et al, 2009). Consistently, we and others have described that Flg ft mice express a truncated and smaller profilaggrin protein that is not processed to filaggrin (Fallon, et al, 2009, Moniaga, et al, 2010, Presland, et al, 2000 (Fig.1).…”

“…Later, the lack of filaggrin in the epidermis was proposed in the commercially available strain of Flg ft mice, which has both Flg and ma mutations, as a model of IV, and therefore there was no discussion about the cutaneous inflammatory conditions from the perspective of AD (Presland, et al, 2000). There have been four recent papers of Flg ft mice as a model of filaggrin deficiency: the first paper used Flg ft mice from which the ma mutation had been eliminated with four additional backcrosses to B6 mice (Fallon, et al, 2009), and the others used the commercially available Flg ft mice (Moniaga, et al, 2010, Oyoshi, et al, 2009, Scharschmidt, et al, 2009). The first report showed only histological abnormality without clinical manifestation (Fallon, et al, 2009), and the second demonstrated spontaneous eczematous skin lesions after 28 weeks of www.intechopen.com age (Oyoshi, et al, 2009), and the third contained no notice of any spontaneous dermatitis in Flg ft mice (Scharschmidt, et al, 2009).…”

“…There have been four recent papers of Flg ft mice as a model of filaggrin deficiency: the first paper used Flg ft mice from which the ma mutation had been eliminated with four additional backcrosses to B6 mice (Fallon, et al, 2009), and the others used the commercially available Flg ft mice (Moniaga, et al, 2010, Oyoshi, et al, 2009, Scharschmidt, et al, 2009). The first report showed only histological abnormality without clinical manifestation (Fallon, et al, 2009), and the second demonstrated spontaneous eczematous skin lesions after 28 weeks of www.intechopen.com age (Oyoshi, et al, 2009), and the third contained no notice of any spontaneous dermatitis in Flg ft mice (Scharschmidt, et al, 2009). The fourth paper by Moniaga et al have demonstrated that Flg ft mice showed spontaneous dermatitis with skin lesions mimicking human AD as early as 5 weeks of age with mild erythema and fine scales and the cutaneous manifestations advanced with age in a steady state under SPF conditions (Moniaga, et al, 2010) (Fig.…”

10-Hydroxy-2-Decenoic Acid in Royal Jelly Extract Induced Both Filaggrin and Amino Acid in a Cultured Human Three-Dimensional Epidermis Model

“…It is thought that filaggrin (FLG) is a main protein which produces the NMF in the stratum corneum, and bears the water-retention ability of the stratum corneum [3]. FLG is a protein of epidermal keratinocytes; at first, a precursor of proFLG was made in the cells of the granular cell layer, which becomes the principal ingredient of keratohyalin granules [4]. When the keratinocyte of the granular cell layer turns into the stratum corneum, it is decomposed and the proFLG turns into FLG [4].…”

“…FLG is a protein of epidermal keratinocytes; at first, a precursor of proFLG was made in the cells of the granular cell layer, which becomes the principal ingredient of keratohyalin granules [4]. When the keratinocyte of the granular cell layer turns into the stratum corneum, it is decomposed and the proFLG turns into FLG [4]. FLG has the action which condenses the keratin fiber of the keratinocyte.…”