Filaggrin in the frontline: role in skin barrier function and disease

TLDR

Loss‑of‑function mutations in FLG, which encode profilaggrin and filaggrin, cause ichthyosis vulgaris, predispose up to 10 % of people to atopic eczema, asthma and allergies, and impair stratum corneum integrity, leading to increased water loss and heightened allergen penetration. During epidermal terminal differentiation, profilaggrin is dephosphorylated and cleaved into filaggrin, which condenses keratin to drive squame formation, and is subsequently citrullinated, unfolding and degrading into hygroscopic amino acids that form part of the natural moisturizing factor. Human genetic studies indicate that reduced or absent filaggrin expression compromises skin barrier function, increasing percutaneous allergen transfer.

Abstract

Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the approximately 400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.