Cell membranes and skin barrier proteins

The skin barrier, primarily located in the stratum corneum, is a complex multi-layered system often described by the "bricks and mortar" model. Corneocytes (the bricks) are protein-enriched cells containing keratin and filaggrin, which are encased in a cornified envelope and surrounded by a lipid matrix (the mortar) composed of ceramides, cholesterol, and free fatty acids. This barrier is essential for preventing transepidermal water loss (TEWL) and protecting the body against environmental pathogens, allergens, and UV radiation. Dysfunction in barrier proteins like filaggrin, loricrin, and involucrin, or alterations in the lipid composition, are central to the pathogenesis of inflammatory skin diseases such as atopic dermatitis and psoriasis. Therapeutic strategies focus on restoring this integrity through topical emollients, physiological lipid replacement, and novel small molecules or biologics that upregulate barrier protein expression or modulate the cytokine environment to allow for natural barrier repair.

Other names

Epidermal barrierSkin permeability barrierStratum corneum barrierCornified envelopeSkin barrier

Drugs targeting the skin barrier work through several mechanisms: occlusion to physically prevent water loss; humectancy to bind moisture within the stratum corneum; physiological lipid replacement to restore the intercellular lipid matrix; and pharmacological upregulation of structural proteins like filaggrin and loricrin via the aryl hydrocarbon receptor (AHR)-OVOL1 signaling axis. Additionally, biologics like dupilumab indirectly restore the barrier by inhibiting Th2 cytokines (IL-4 and IL-13) that normally downregulate essential barrier proteins.