Trehalose Prevents IL-4/IL-13–Induced Skin Barrier Impairment by Suppressing IL-33 Expression and Increasing NRF2 Activation in Human Keratinocytes In Vitro

Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis (AD). At high concentrations, the nonreducing disaccharide α-d-glucopyranosyl α-d-glucopyranoside (trehalose) induces a transient senescence-like state in fibroblasts and promotes wound repair. Here, we investigated the effect of trehalose on normal human keratinocytes (KCs) and demonstrated its specific role in the skin barrier. RNA-seq analysis revealed that trehalose regulates the expression of many skin-barrier-associated genes. T helper 2 (Th2) cytokines interleukin (IL)-4/IL-13 were observed to downregulate several differentiation markers (FLG, LOR, K1, and K10) and epidermal antimicrobial proteins in monolayer-cultured KCs and living skin equivalents (LSE), and impaired skin barrier function in LSE, all of which were significantly upregulated or restored by trehalose. Trehalose inhibited IL-33 expression and reduced nuclear IL-33 levels by activating MEK5-extracellular signal-regulated kinase 5 (ERK5) and suppressing MEK1/2-ERK pathway. It also increased nuclear factor erythroid 2-related factor 2 (Nrf2) activation to trigger antioxidant enzyme production via c-Jun N-terminal kinase (JNK), thus, neutralizing IL-4/IL-13-mediated oxidative stress. Trehalose prevented IL-4/IL-13-mediated signal transducer and activator of transcription (STAT)3/STAT6 activation and restored IL-4/IL-13-suppressed skin barrier molecules via IL-33 downregulation and Nrf2 activation. This study demonstrated that trehalose may play a role in skin barrier repair in AD.