Revisiting the Roles of Filaggrin in Atopic Dermatitis

Abstract

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.

Keywords: NMF; atopic dermatitis; epidermis; filaggrin; microbiome; pH.

Figure 1

Evolution and distribution of profilaggrin and filaggrin during epidermal differentiation: dark gray disks containing profilaggrin are keratohyalin granules present in the cytoplasm of granular KCs. Under the action of phosphatases, proteases, and Ca²⁺, profilaggrin is expelled in the cytoplasm and degraded into filaggrin monomers (small orange disks). Green lines are keratin filaments aggregated by filaggrin monomers in the lower SC. Under the action of transglutaminases (TGMs), filaggrin molecules may be covalently linked to the cornified envelope. In the upper SC, filaggrin is further processed into free amino acids by the sequential action of peptidylarginine deaminases and proteases, producing the Natural Moisturizing Factor (NMF, green squares and orange triangles). The left part of the figure is a hematoxylin–eosin staining of a healthy human epidermis; arrows show the dermis–epidermis junction.

Figure 2

Control of profilaggrin and filaggrin processing in atopic dermatitis: summary of data collected in mouse models and patients with atopic dermatitis. Changes in protein amounts in atopic skin is shown by using a color code (orange, increase; green, decrease). Enzymes written in bold show regulation consistent with modulation of amounts of profilaggrin and filaggrin observed in atopic skin [30,120,140,141,145,146,147,148]. * Only studied in mice. PEP1, profilaggrin endoproteinase 1; LEKTI, lympho-epithelial Kazal-type-related inhibitor; MT-SP1, matriptase; UCA, urocanic acid; PCA, pyrrolidone carboxylic acid.

Figure 3

Summary of filaggrin regulation and roles in atopic dermatitis: experimentally confirmed roles (darkest boxes, white writing) versus prevailing ideas, most of them unsubstantiated. Decreased parameters are in green boxes, and increased parameters are in orange boxes.