title: Permeability barrier disorder in Niemann-Pick disease: sphingomyelin-ceramide processing required for normal barrier homeostasis.
abstract: Prior studies have established the requirement for enzymatic hydrolysis of glucosylceramides to ceramide for epidermal barrier homeostasis. In this study, we asked whether sphingomyelin-derived ceramide, resulting from acid-sphingomyelinase activity, is also required for normal barrier function. We showed first, that a subset of Niemann-Pick patients with severe acid-sphingomyelinase deficiency (i.e., <2% residual activity) demonstrate abnormal permeability barrier homeostasis, i.e., delayed recovery kinetics following acute barrier disruption by cellophane tape-stripping. To obtain further mechanistic insights into the potential requirement for sphingomyelin-to-ceramide processing for the barrier, we next studied the role of acid-sphingomyelinase in hairless mouse skin. Murine epidermis contains abundant acid-sphingomyelinase activity (optimal pH 5.1-5.6). Two hours following acute barrier disruption by tape-stripping, acid-sphingomyelinase activity increases 1. 44-fold (p<0.008 versus vehicle-treated controls), an increase that is blocked by a single topical application of the acid-sphingomyelinase inhibitor, palmitoyldihydrosphingosine. Furthermore, both palmitoyldihydrosphingosine and desipramine, a chemically and mechanically unrelated acid-sphingomyelinase inhibitor, significantly delay barrier recovery both 2 and 4 h after acute barrier abrogation. Inhibitor application also causes both an increase in sphingomyelin content, and a reduction of normal extracellular lamellar membrane structures, in the stratum corneum. Both of the inhibitor-induced delays in barrier recovery can be overridden by co-applications of topical ceramide, demonstrating that an alteration of the ceramide-sphingomyelin ratio, rather than sphingomyelin accumulation, is likely responsible for the barrier abnormalities that occur with acid-sphingomyelinase deficiency. These studies demonstrate an important role for enzymatic processing of sphingomyelin-to-ceramide by acid-sphingomyelinase as a mechanism for generating a portion of the stratum corneum ceramides for permeability barrier homeostasis in mammalian skin.
authors.affiliation: Departments of Dermatology and Medicine, School of Medicine and Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Schmuth
authors.forename: M Q
authors.initials: MQ
authors.lastname: Man
authors.forename: F
authors.initials: F
authors.lastname: Weber
authors.forename: W
authors.initials: W
authors.lastname: Gao
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
authors.forename: P
authors.initials: P
authors.lastname: Fritsch
authors.forename: P M
authors.initials: PM
authors.lastname: Elias
authors.forename: W M
authors.initials: WM
authors.lastname: Holleran
mesh_terms: D000293:Adolescent; D000328:Adult; D002463:Cell Membrane Permeability / Q000502:physiology; D002518:Ceramides / Q000502:physiology*; D002648:Child; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009542:Niemann-Pick Diseases / Q000503:physiopathology*; D012867:Skin / Q000166:cytology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013109:Sphingomyelins / Q000502:physiology*
chemical_list: D002518:Ceramides; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase