Permeability barrier disorder in Niemann-Pick disease: Sphingomyelin-ceramide processing required for normal barrier homeostasis

Prior studies have established the requirement for enzymatic hydrolysis of glucosylceramides to ceramide for epidermal barrier homeostasis. In this st udy, we asked whether sphingomyelin-derived ceramide, resulting from acid-s phingomyelinase activity, is also required for normal barrier function. We showed first, that a subset of Niemann-Pick patients with severe acid-sphin gomyelinase deficiency (i.e., <2% residual activity) demonstrate abnormal p ermeability barrier homeostasis, i.e., delayed recovery kinetics following acute barrier disruption by cellophane tape-stripping. To obtain further me chanistic insights into the potential requirement for sphingomyelin-to-cera mide processing for the barrier, we next studied the role of acid-sphingomy elinase in hairless mouse skin. Murine epidermis contains abundant acid-sph ingomyelinase activity (optimal pH 5.1-5.6). Two hours following acute barr ier disruption by tape-stripping, acid-sphingomyelinase activity increases 1.44-fold (p<0.008 versus vehicle-treated controls), an increase that is bl ocked by a single topical application of the acid-sphingomyelinase inhibito r, palmitoyldihydrosphingosine. Furthermore, both palmitoyldihydrosphingosi ne and desipramine, a chemically and mechanically unrelated acid-sphingomye linase inhibitor, significantly delay barrier recovery both 2 and 4 h after acute barrier abrogation. Inhibitor application also causes both an increa se in sphingomyelin content, and a reduction of normal extracellular lamell ar membrane structures, in the stratum corneum. Both of the inhibitor-induc ed delays in barrier recovery can be overridden by co-applications of topic al ceramide, demonstrating that an alteration of the ceramide-sphingomyelin ratio, rather than sphingomyelin accumulation, is likely responsible for t he barrier abnormalities that occur with acid-sphingomyelinase deficiency. These studies demonstrate an important role for enzymatic processing of sph ingomyelin-to-ceramide by acid-sphingomyelinase as a mechanism for generati ng a portion of the stratum corneum ceramides for permeability barrier home ostasis in mammalian skin.