The discovery in 2006 that loss-of-function mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris and can predispose to atopic dermatitis (AD) galvanized the dermatology research community and shed new light on a skin protein that was first identified in 1981. However, although outstanding work has uncovered several key functions of filaggrin in epidermal homeostasis, a comprehensive understanding of how filaggrin deficiency contributes to AD is still incomplete, including details of the upstream factors that lead to the reduced amounts of filaggrin, regardless of genotype. In this review, we re-evaluate data focusing on the roles of filaggrin in the epidermis, as well as in AD. Filaggrin is important for alignment of keratin intermediate filaments, control of keratinocyte shape, and maintenance of epidermal texture via production of water-retaining molecules. Moreover, filaggrin deficiency leads to cellular abnormalities in keratinocytes and induces subtle epidermal barrier impairment that is sufficient enough to facilitate the ingress of certain exogenous molecules into the epidermis. However, although FLG null mutations regulate skin moisture in non-lesional AD skin, filaggrin deficiency per se does not lead to the neutralization of skin surface pH or to excessive transepidermal water loss in atopic skin. Separating facts from chaff regarding the functions of filaggrin in the epidermis is necessary for the design efficacious therapies to treat dry and atopic skin.

Atopic dermatitis (AD) is an inflammatory skin disease in which epidermal barrier impairment, often owing to FLG null mutations, precedes immune hyperresponsiveness. Ichthyosis vulgaris is characterized by FLG null mutations and noninflamed dry skin. Netherton syndrome (NS), caused by SPINK5 null mutations, is characterized by generalized erythroderma with scaling and atopic manifestations. The goal of this work was to evaluate associations between specific skin disease features, such as ichthyotic and/or atopic manifestations, and the skin bacterial and fungal microbiota. Taxon diversity showed greater variation in the bacterial microbiota than in the fungal microbiota in the skin diseases. The relative abundances of Firmicutes (Staphylococcus) and Actinobacteria (Corynebacterium) were augmented in ichthyosis vulgaris, AD, and NS, whereas those of Proteobacteria/Enhydrobacter and Bacteroidetes were reduced, regardless of body site. Furthermore, proportions of Staphylococcus were correlated with transepidermal water loss and serum IgE levels. Nevertheless, the skin of patients with low to mild AD was overcolonized with Staphylococcus epidermidis and not with Staphylococcus aureus. Ascomycota were increased in both AD and NS, but from expansion of different fungal species. Finally, the expansion of pathologic bacteria in AD and NS might be supported by surrounding fungi. Thus, distinguishable bacterial and fungal skin dysbiosis in AD, NS, and ichthyosis vulgaris emphasizes disease-specific pathomechanisms.