Ceramide signaling in mammalian epidermis

Abstract

Ceramide, the backbone structure of all sphingolipids, as well as a minor component of cellular membranes, has a unique role in the skin, by forming the epidermal permeability barrier at the extracellular domains of the outermost layer of the skin, the stratum corneum, which is required for terrestrial mammalian survival. In contrast to the role of ceramide in forming the permeability barrier, the signaling roles of ceramide and its metabolites have not yet been recognized. Ceramide and/or its metabolites regulate proliferation, differentiation, and apoptosis in epidermal keratinocytes. Recent studies have further demonstrated that a ceramide metabolite, sphingosine-1-phosphate, modulates innate immune function. Ceramide has already been applied to therapeutic approaches for treatment of eczema associated with attenuated epidermal permeability barrier function. Pharmacological modulation of ceramide and its metabolites' signaling can also be applied to cutaneous disease prevention and therapy. The author here describes the signaling roles of ceramide and its metabolites in mammalian cells and tissues, including the epidermis. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Keywords: Ceramide; Epidermis; Keratinocyte; Signaling; Sphingolipid.

Fig. 1

Roles of Ceramide and Its Metabolites in Epidermis Glycosphingolipid lipids, ceramide metabolites, also are signaling lipid (not included in this figure, see 7 and 9.3, below)

Fig. 2

Ceramide (N-octadecanoyl sphingosine) Structure Ceramides in the stratum corneum show structural variation, including hydroxylation (α, ω, 4, and 6 position). Sphingosine (carbon chain lengths 18–20) and non-hydroxy fatty acids (carbon chain length 16–24) are major ceramide constituents in mammalian cells and these major ceramdie species ubiquitously serve as signaling lipid in mammalian cells, including epidermis.

Fig. 3

Ceramide Metabolic Pathway in Epidermis

Fig. 4

Protective Mechanism Against Ceramide-Induced Apoptosis in Response to Oxidative Stress in Epidermis Toxic levels of stress overwhelms these protective mechanism and results in increased apoptosis [93]. Since CERT (ceramide-transfer protein) forms stable homotrimer that diminishes ceramide transfer function under oxidative stress, sphingomyelin synthesis does not increase [104].

Fig. 5

Ceramide metabolite, sphingosine-1-phosphate signals to stimulate antimicrobial defense.

Fig. 6

Signalings of ceramide and its metabolites to alter cellular functions in normal keratinocytes