br Conclusion It is essential to investigate the

Conclusion It is essential to investigate the mutual association between permeability barrier dysfunction and allergic inflammation to clarify the pathogenesis of AD. Such investigations could not only elucidate the complicated pathogenesis in which genetic abnormalities and environmental factors collaborate in a sophisticated manner, but also sow the seeds of new scientific and therapeutic strategies in AD (Figure 1).
Introduction Ceramide (Cer) is composed of long-chain aminoalcohol and amide-linked fatty acids, whose chain lengths are 18–20 and 16–24, respectively (Figure 1). Cer serves as a membrane constituent and also as the backbone of all complex sphingolipids. It is converted to metabolites, and Cer and its metabolites regulate cellular functions (Figure 2). In skin, Cer serves as a key component in the epidermal permeability barrier in the stratum corneum. We review the signaling roles of Cer and its metabolites in skin. To distinguish between Cer forming epidermal permeability barrier structures and Cer regulating cellular function, the former and the latter are referred to as “barrier Cer” and “signaling Cer,” respectively.
Ceramide for epidermal permeability barrier An epidermal permeability barrier is required for survival of mammals living in dry terrestrial environments. Major barrier lipids consist of cholesterol, free fatty acid, and Cer, which localizes in the extracellular lipids in the stratum corneum and is a key permeability barrier constituent. At least nine molecular ctap of Cer, in both bulk amounts and molecular heterogeneity, located in the stratum corneum are unique to skin. Prior studies show that decreased contents of Cer and/or alteration of molecular species occur in some cutaneous diseases associated with permeability barrier abnormality, i.e., atopic dermatitis (AD), psoriasis, and certain ichthyoses. Furthermore, it has been recently demonstrated that a minor Cer metabolite species, sphingosine, also contributes to form a competent permeability barrier structure.
Differences between Cer for epidermal permeability barrier and Cer for signaling The differences between Cer responsible for permeability barrier formation in the stratum corneum and signaling Cer are summarized below.
Ceramide metabolites Cer is converted into four metabolic pathways (Figure 3). Four isoforms of ceramidase—(1) acidic ceramidase distributed in lysosome; (2) neutral ceramidase in plasma membrane and ER; (3) alkaline ceramidase 2 (so-called skin ceramidase) in ER and alkaline ceramidase 3 in Golgi apparatus; (4) phytoalkaline ceramidase (alkaline ceramidase 1) in ER—have been identified in mammals. Alkaline ceramidase 2 has been shown only in differentiated layers in the epidermis. Four ceramidase isoforms are present in keratinocytes, whereas both acidic and alkaline ceramidase 2 levels are increased and alkaline ceramidase 1 levels are decreased during keratinocyte differentiation. The other three ceramidase levels are not changed in a differentiation-dependent manner. Moreover, glycosylceramides are further glycosylated to di- or polyglycosylceramide. In the epidermis, glucosylceramides are a major species. Sphingosine is phospholyated to sphingosine-1-phosphate (S1P) by sphingosine kinase 1 or 2. Signaling Cer can be produced from hydrolyses of sphingomyelin or glucosylceramide, by sphingomyelinase or β-glucocerebrosidase, respectively, as well as de novo synthesis by activation of either serine-palimitoyltransferase or ceramide synthase. In contrast to the sphingomyelin pathway that generates signaling Cer, the glucosylceramide pathway has not been elucidated. Our prior studies demonstrated that Cer production is increased following ultraviolet (UV) B irradiation or other oxidative stressors and results in increasing Cer-induced apoptosis in keratinocytes. Both toxic (high doses) and subtoxic (low doses) increased ceramide, whereas toxic levels of irradiation sustained elevated Cer; however, Cer was restored toward normal levels in cells treated with subtoxic levels of UVB because of its efficient conversion into nonapoptotic Cer metabolites, suggesting that metabolic conversion contributes to protecting cells against Cer-induced apoptosis. Cer-induced apoptosis is in part a mechanism of chemotherapy, whereas accelerating metabolic conversion of Cer to glucosylceramide and S1P-attenuating chemotherapy has been shown in several types of tumor cells, including melanoma. In particular, the chemotherapy-resistant tumor cells often show increased enzyme production, which is responsible for the metabolic protective mechanism against Cer-induced apoptosis.