Anti-Inflammatory and skin barrier-improving effects of lipimoide in relation to epidermal TRPM8 upregulation

Introduction: The skin serves as a barrier, preventing internal moisture loss and protecting against the invasion of external harmful factors while also playing a role in immune responses. Barrier disruption is a hallmark of inflammatory skin diseases characterized by dryness and itching, notably in conditions like atopic dermatitis (AD). Recent research has focused on exploring novel compounds that can enhance skin barrier function and modulate inflammatory responses. Therefore, this study aimed to investigate the barrier-protective role and underlying mechanisms of lipimoide in an AD-like skin barrier impairment model using normal human keratinocytes (NHKs) and human skin equivalent models. Method: An in vitro AD-like condition was induced in NHEKs and a human skin equivalent models by treating with a stimulus cocktail containing Th2 cytokines (IL-4 and IL-13), leading to impaired keratinocyte differentiation, increased inflammation, and epidermal thickening. Functional studies on skin barrier function, anti-inflammatory effects, and the molecular mechanisms involving TRPM8 expression were conducted using RT-qPCR, Western blotting, immunofluorescence analysis, immunohistochemistry, and transepithelial electrical resistance (TEER) measurements to assess skin barrier integrity. Results: Treatment with lipimoide, a novel synthetic compound, increased the gene and protein expression of TRPM8, which had been downregulated in NHEKs and skin equivalents induced by the stimulus cocktail. Additionally, lipimoide was found to restore the expression of epidermal differentiation markers, reduce inflammation, and enhance skin barrier function in AD-like skin conditions. Conclusion: This study indicates that TRPM8 plays a crucial role in maintaining skin barrier integrity and may serve as a therapeutic target for treating dermatitis in AD. Furthermore, as a TRPM8 modulator, lipimoide promotes epidermal barrier homeostasis and function, providing a potential therapeutic strategy for managing dry and inflammatory skin conditions.