Highly concentrated trehalose prevents IL-4/IL-13-induced skin barrier impairment by suppressing IL-33 expression and increasing Nrf2 activation in epidermal keartinocytes

Skin barrier dysfunction initiates or deteriorates various cutaneous problems, such as atopic dermatitis (AD). In high concentrations, the nonreducing disaccharide α-d-glucopyranosyl α-d-glucopyranoside (trehalose) can induce transient senescence-like state in fibroblasts and promote wound repair. Here we have investigated the direct effect of a high concentration of trehalose on primary human keratinocytes (KCs) and demonstrated its specific role in the skin barrier. RNA-seq analysis revealed that trehalose regulates many skin-barrier-associated genes in T helper 2 (Th2) cytokines interleukin (IL)-4/IL-13-treated and -untreated KCs. Using monolayer-cultured post-confluent normal human KCs and living skin equivalent (LSE), we identified IL-4/IL-13-downregulated differentiation markers and various epidermal antimicrobial proteins, all of which were significantly upregulated or restored by trehalose (60 mg/mL). Trehalose inhibited IL-33 expression and reduced nuclear IL-33 by activating MEK5- extracellular signal-regulated kinase (ERK)-5 and suppressing MEK1/2-ERK pathways. It also increased nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase 1 (HMOX1) activation 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 and STAT6 activation and restored various skin barrier molecules reduced by IL-4/IL-13 via IL-33 downregulation and Nrf2-HMOX1 activation. This study demonstrates that trehalose might play salubrious roles as skin barrier repair in AD.