A unique ceramide synthase is absolutely required for skin barrier functions

The primary function of the epidermis is to provide a defensive barrier against pathogenic microbes, xenobiotics and most importantly to shield terrestrial vertebrates against desiccation. This essential permeability barrier mainly resides in the stratum corneum, where corneocytes are embedded in continuous lipid lamellar sheets covalently bound to proteins of the cornified envelope. Sphingolipids play a key role in maintaining epidermal barrier homeostasis. On one hand, ceramides are major components of the extracellular lipid lamellae and the corneocyte-lipid envelope required for the water permeability barrier of the skin. On the other hand, their direct metabolites, e.g. (phyto)sphingosines are discussed to contribute to the defensive barrier towards pathogenic infections.

Our current investigations with in vitro living cell culture and in vivo mouse models has led to the identification of the unique mammalian ceramide synthase absolutely required for ultra long chain ceramide synthesis. Its loss of function in mice results in a complete lack of ceramides covalently linked to linoleic acid or to proteins of the corneocyte-lipid envelope. Consequently, 90% of all epidermal ceramides are absent. In the extracellular space, mutant mice fail to establish continuous lipid lamellae thus leading to a severely increased transepidermal water loss and ultimately to neonatal death. From our ultrastructural and immunofluorescent analyses, we conclude loss of epidermal sphingolipids to trigger a keratinocyte differentiation arrest at an embryonic pre-barrier stage.