Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis

Abstract

Background Ceramide hydrolysis by ceramidase in the stratum corneum (SC) yields both sphingoid bases and free fatty acids (FFA). While FFA are key constituents of the lamellar bilayers that mediate the epidermal permeability barrier, whether sphingoid bases influence permeability barrier homeostasis remains unknown. Pertinently, alterations of lipid profile, including ceramide and ceramidase activities occur in atopic dermatitis (AD). Object We investigated alterations in sphingoid base levels and/or profiles (sphingosine to sphinganine ratio) in the SC of normal vs. AD mice, a model that faithfully replicates human AD, and then whether altered sphingoid base levels and/or profiles influence(s) membrane stability and/or structures. Methods Unilamellar vesicles (LV), incorporating the three major SC lipids (ceramides/FFA/cholesterol) and different ratios of sphingosine/sphinganine, encapsulating carboxyfluorescein, were used as the model of SC lipids. Membrane stability was measured as release of carboxyfluorescein. Thermal analysis of LV was conducted by Differential scanning calorimetry (DSC). Results LV containing AD levels of sphingosine/sphinganine (AD-LV) displayed altered membrane permeability vs. normal-LV. DSC analyses revealed decreases in orthorhombic structures that form tightly-packed lamellar structures in AD-LV. Conclusion Sphingoid base composition influences lamellar membrane architecture in SC, suggesting that altered sphingoid base profiles could contribute to the barrier abnormality in AD.

Sweat lipid mediator profiling: a noninvasive approach for cutaneous research

“…Subjects with AD showed elevated concentrations of [NS] (25,26). More recently, increases in C18:1 sphingosine have also been shown to be associated with increases in membrane permeability in an AD mouse model (27).…”

Epithelial barrier dysfunctions in atopic dermatitis: a skin-gut-lung model linking microbiome alteration and immune dysregulation

“…Ceramides (CERs), free fatty acids (FFAs) and cholesterol comprise the main SC lipids, of which CERs are the most abundant . CERs are a critical component of the lipid matrix that aids in preventing TEWL . In AD, there is decreased total CER content and alteration in CER chain length .…”

Recent advances in atopic dermatitis and psoriasis: Genetic background, barrier function, and therapeutic targets

“…Ceramide hydrolysis by ceramidase in SC yields both sphingoid bases and free fatty acids. Recent study revealed that sphingoid base composition influences lamellar membrane architecture in SC, suggesting that altered sphingoid base profiles could contribute to the barrier abnormality in AD [10]. Pyrrolidone carboxylic acid (PCA), a natural moisturizing factor, and caspase-14, which cleaves filaggrin monomers to free amino acids and their derivatives such as PCA, are also important for skin barrier.…”