Acylceramide is a key player in skin barrier function: insight into the molecular mechanisms of skin barrier formation and ichthyosis pathogenesis

Abstract

For a quarter of the century, tremendous advances have been achieved in our understanding of the pathogenic mechanisms and relevant genetic defects underlying ichthyoses and ichthyosis syndromes. Research on the pathogenic mechanisms of ichthyoses has provided novel insights into the synthesis and metabolism of epidermal ceramides. Conversely, our advanced understanding of the dynamics of ceramides in the epidermis has contributed to the clarification of the ichthyosis pathogenesis. Most ichthyosis subtypes have pathogenic processes related to stratum corneum barrier defects. Two essential structures of the stratum corneum barrier, the corneocyte lipid envelope (CLE) and the intercellular lipid layers, consist of epidermal functional lipids. Ceramides are included in the most significant components of the functional lipid in the epidermis. Acylceramides, particularly EOS, which is a combination of esterified ω-hydroxy ultra-long-chain fatty acids and sphingosines, are critical as the main component of the CLE. Molecules encoded by a number of ichthyosis-causative genes (ABCA12, ALOXE3, ALOX12B, CYP4F22, CERS3, ABHD5, PNPLA1, ELOVL4, and SDR9C7) are known to be involved in the synthesis, transport, and metabolism of acylceramide, and in the formation of the CLE. This review focuses on the processes of acylceramide biosynthesis and the steps of CLE formation in the stratum corneum. I sum up the pathogenic mechanisms of autosomal recessive congenital ichthyosis and various ichthyosis syndromes from the viewpoints of the defective synthesis, metabolism, and transport of acylceramide and the failure of CLE formation.