Early-life regional and temporal variation in filaggrin-derived natural moisturizing factor, filaggrin-processing enzyme activity, corneocyte phenotypes and plasmin activity: implications for atopic dermatitis

BackgroundFilaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin-processing enzymes [bleomycin hydrolase (BH) and calpain-1 (C-1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown. ObjectivesWe conducted a cross-sectional, observational study investigating regional and age-dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life. MethodsWe measured NMF using a tape-stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C-1 and plasmin activities were determined. ResultsNMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek corneocytes remain immature. Plasmin, BH and C-1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin. ConclusionsRegional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD. What's already known about this topic? Atopic dermatitis (AD) frequently starts in early infancy, and the first eczematous lesions emerge on the cheeks. Filaggrin is a major structural protein in the stratum corneum (SC). Filaggrin deficiency is associated with the development of AD and, in the context of AD, food allergies and asthma. Filaggrin is metabolized into natural moisturizing factors (NMFs), which can be measured in the SC. What does this study add? Regional differences in NMF levels, corneocyte envelope immaturity and protease activities may help explain why infantile AD most often initially affects the cheeks. Filaggrin processing, corneocyte maturity, and protease activities show regional and temporal differences in infant skin. These findings may explain disease patterns in early-life AD. What is the translational message? Cheek skin may be highly relevant for allergen priming. Emollient therapy at the vulnerable cheek site might help to prevent AD and/or food sensitization. Linked Editorial:Thyssen. Br J Dermatol 2018; 179:235-236. Plain language summary available online Respond to this article