Sphingosylphosphorylcholine is upregulated in the stratum corneum of patients with atopic dermatitis

Abstract

To clarify the functional relevance of sphingomyelin (SM) deacylase to the ceramide deficiency seen in atopic dermatitis (AD), we developed a new highly sensitive method and measured the metabolic intermediate sphingosylphosphorylcholine (SPC) that accumulates in the stratum corneum. SPC in intercellular lipids extracted from stratum corneum was reacted with [ 14 C]acetic anhydride to yield [ 14 C-C 2 ]SM, which was then analyzed by TLC. In both the lesional and non-lesional stratum corneum obtained from patients with AD, there was a significant increase in the content of SPC over that of healthy control subjects. There was a reciprocal relationship between increases in SPC and decreases in ceramide levels of stratum corneum obtained from healthy controls, and from lesional and non-lesional skin from patients with AD. Comparison with other sphingolipids present in the stratum corneum demonstrated that there is a significant positive correlation between SPC and glucosylsphingosine, another lysosphingolipid derived from glucosylceramide by another novel epidermal enzyme, termed glucosylceramide deacylase. In contrast, there was no correlation between SPC and sphingosine, a degradative product generated from ceramide by ceramidase. These findings strongly suggest the physiological relevance of SM deacylase function in vivo to the ceramide deficiency found in the skin of patients with AD. Intercellular lipids in the stratum corneum have been implicated as important determinants in the water-retaining properties (1, 2) and in the barrier function (3, 4) of the skin. Ceramides are major constituents of intercellular lipids, comprising more than 50% of them. Previously, we demonstrated that there is a marked reduction in the amount of ceramides in the stratum corneum in lesional and in non-lesional forearm skin of patients with atopic dermatitis (AD) (5), which suggested that the ceramide deficiency is an important etiologic factor for the barrierdisrupted and dry skin seen in AD. Subsequently, we found that the causative factor behind the ceramide deficiency in the stratum corneum of patients with AD is an abnormal expression of sphingomyelin (SM) deacylase in their epidermis (6). This enzyme hydrolyzes SM at the acyl site to yield free fatty acid and sphingosylphosphorylcholine (SPC) instead of the formation of ceramide and phosphorylcholine (PC) by sphingomyelinase (SMase). Direct enzymatic analysis of the stratum corneum or of the epidermis of patients with AD revealed that there are 9-fold or 3-fold increases, respectively, in the activity of SM deacylase in patients with AD compared with healthy normal controls (7). The sum of those findings demonstrates that the novel epidermal enzyme SM deacylase is expressed at high levels in the epidermis of patients with AD. The competition of this enzyme with SMase for the common substrate SM leads to the ceramide deficiency in the stratum corneum of patients with AD. Thus in this study, in order to clarify the physiologic and functional relevance of SM deacylase t...

Glucosylsphingosine Induces Itch-Scratch Responses in Mice

“…The identification of pruritogen is one of ways to clarify the mechanism of pruritus and clues for therapeutics. Gsp is upregulated in the lesional skin of patients from atopic dermatitis (Okamoto et al, 2003). We speculate that abnormal skin barrier itself contributed to the symptoms of atopic dermatitis.…”

“…The activity of sphingomyelin deacylase, in fact, is markedly higher in patients with atopic dermatitis than in healthy individuals. Glucosylsphingosine (Gsp) is increased in skin of patients with atopic dermatitis (Okamoto et al, 2003). Gsp, a metabolic precursor of glucocerebroside synthesis, also accumulates in the cerebral and cerebellar cortex in patients both with type 2 and 3 Gaucher disease (Nilsson and Svennerholm, 1982;Orvisky et al, 2002).…”

Dissociation of Calmodulin-Target Peptide Complexes by the Lipid Mediator Sphingosylphosphorylcholine

“…We have shown that the putative lipid second messenger sphingosylphosphorylcholine (SPC) (12,13) binds specifically to both apo-and Ca 2ϩ -saturated CaM, and inhibits the action of the protein on the target enzymes phosphodiesterase and calcineurin (14). Data on SPC metabolism is still scarce, but its presence has been demonstrated under several physiologic and pathologic conditions (15)(16)(17)(18). Our findings suggest a novel endogenous regulation for CaM and also proposes that CaM might be an intracellular receptor for the sphingolipid.…”

“…The interactions it can actually modify in vivo are probably selected by their cellular localization. Currently our knowledge of SPC metabolism is scarce (15)(16)(17)(18), so to accurately address this question, further study into the mechanism and location of in vivo SPC production is necessary. Nevertheless, experiments carried out with micelles containing other lipids besides SPC confirmed that SPC can displace CaM from its targets even when incorporated into a mixed lipid environment.…”

Potential New Therapeutic Targets for Pathological Pruritus

“…In patients with atopic dermatitis, the amount of ceramide in the stratum corneum decreases, and there is an inverse correlation between ceramide and sphingosylphosphorylcholine (SPc) levels in the lesional stratum corneum. 29) In the epidermis of patients with atopic dermatitis, the activity of sphingomyelin glucosylceramide deacylase is increased, and sphingomyelin and glucocerebroside are converted to SPc and glucosylsphingosine, respectively, by this enzyme, which results in the decrease in ceramide, leading to skin dryness and the disruption of the skin barrier. 30) SPc downregulates filaggrin gene transcription, which also leads to skin dryness and the disruption of the skin barrier.…”