Repetin Regulates Epidermal Barrier Homeostasis and Is Associated With Inflammatory Skin Diseases

Repetin (RPTN) is a member of the fusion S100 protein family encoded within the epidermal differentiation complex. Although genetic studies have revealed that RPTN is a susceptibility gene for atopic dermatitis (AD), its biological function remains poorly understood. In this study, we investigated the role of RPTN in epidermal homeostasis and inflammatory skin diseases. We examined RPTN expression in normal skin, inflammatory skin diseases, and differentiated normal human keratinocytes (NHKs). Functional analyses were performed using RPTN knockdown (KD) NHK and three-dimensional (3D) skin-equivalent models. Epidermal barrier function was assessed using a lucifer yellow permeability assay, and cytokine-mediated regulation of RPTN expression was evaluated using 3D atopic dermatitis (AD) and psoriasis models. RPTN was primarily expressed in the granular layer of the normal epidermis and increased with keratinocyte differentiation. In the 3D skin-equivalent model, RPTN deficiency impaired epidermal barrier function and induced the expression of differentiation-related genes, including FLG, IVL, TGM1, CLDN1, KLK7, ALOX12, and TCHHL1. Notably, RPTN knockdown significantly increased IL-25 expression. RPTN expression was elevated in chronic atopic dermatitis (AD) lesions and in hypergranular epithelia of psoriasis vulgaris, lichen planus, and epidermolytic ichthyosis. In a 3D AD model, IL-4 and IL-13 significantly induced RPTN expression. These findings indicate that RPTN contributes to maintaining epidermal barrier homeostasis and suggest that it may be associated with regulating inflammatory responses.