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Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment.

Checa A, Xu N, Sar DG, Haeggström JZ, Ståhle M, Wheelock CE - Sci Rep (2015)

Bottom Line: Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin.In addition, the effects of anti-TNF-α treatment were determined.The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry 2, Karolinska Institutet, SE-17177, Stockholm, Sweden.

ABSTRACT
Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001; n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

No MeSH data available.


Related in: MedlinePlus

Circulating sphingoid bases are increased in severe psoriasis patients.(a–d) Plasma levels of sphingoid bases are increased in severe psoriasis patients (n = 32) in comparison to healthy controls (n = 32) and mild psoriasis patients (n = 32). Each point represents an individual. A horizontal line shows the mean value for the group. (e–h) Levels of sphingoid bases are not affected by anti-TNF-α treatment in severe psoriasis patients (n = 16). Connected dots represent one individual. Normality was assessed by the Kolmogorov-Smirnov test. The statistical significance for multiple group comparisons was determined via a one way ANOVA with Tukey’s post-hoc correction. Pairwise comparisons were performed using the Wilcoxon signed-rank test. ***P < 0.001, NS = Not significant.
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f1: Circulating sphingoid bases are increased in severe psoriasis patients.(a–d) Plasma levels of sphingoid bases are increased in severe psoriasis patients (n = 32) in comparison to healthy controls (n = 32) and mild psoriasis patients (n = 32). Each point represents an individual. A horizontal line shows the mean value for the group. (e–h) Levels of sphingoid bases are not affected by anti-TNF-α treatment in severe psoriasis patients (n = 16). Connected dots represent one individual. Normality was assessed by the Kolmogorov-Smirnov test. The statistical significance for multiple group comparisons was determined via a one way ANOVA with Tukey’s post-hoc correction. Pairwise comparisons were performed using the Wilcoxon signed-rank test. ***P < 0.001, NS = Not significant.

Mentions: Using ultra performance liquid chromatography—tandem mass spectrometry (UPLC-MS/MS), we quantified the sphingolipid levels in the plasma of patients with mild (n = 32) or severe psoriasis (n = 32) and healthy donors (n = 32) (Table 1). In addition, levels of circulating sphingolipids were determined in 16 of the severe psoriasis patients after 12 weeks of treatment with the anti-TNF-α drug Etanercept. Sphingolipids are discussed in terms of the lipid class (e.g, hexosylceramides) and the associated fatty acid chain (e.g., palmitic acid). The fatty acid nomenclature depends upon the length of the alkyl chain and degree of unsaturation. For example, lauric acid contains a 12 carbon saturated alkyl chain (C12:0) and nervonic acid possesses a 24 carbon alkyl chain with a single double bond (C24:1). Because of their high abundance in plasma, our analysis focused on the NS class of sphingolipids. In addition, NS is one of only two sphingomyelin classes that can produce ceramides by hydrolysis in the stratum corneum. Our analysis included extensive coverage of the sphingolipid pathway (30 species in total were quantified), consisting of a range of compounds including sphingomyelins, ceramides, hexosylceramides, lactosylceramides and dihydroceramides with varying fatty acid chain lengths (Supplementary Table 1). The analysis also included free phosphorylated and non-phosphorylated NS sphingoid bases (sphingosine, sphinganine, S1P and sphinganine-1-phosphate [Spa1P]). Supplementary Figure 1 provides an overview of sphingolipid metabolism. Circulating levels of sphingosine, S1P, sphinganine and Spa1P were significantly elevated (P < 0.001) in severe psoriasis patients compared with healthy controls and mild psoriasis groups. There were no significant differences between the healthy individuals and patients with mild psoriasis (Fig. 1a–d).


Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-α treatment.

Checa A, Xu N, Sar DG, Haeggström JZ, Ståhle M, Wheelock CE - Sci Rep (2015)

Circulating sphingoid bases are increased in severe psoriasis patients.(a–d) Plasma levels of sphingoid bases are increased in severe psoriasis patients (n = 32) in comparison to healthy controls (n = 32) and mild psoriasis patients (n = 32). Each point represents an individual. A horizontal line shows the mean value for the group. (e–h) Levels of sphingoid bases are not affected by anti-TNF-α treatment in severe psoriasis patients (n = 16). Connected dots represent one individual. Normality was assessed by the Kolmogorov-Smirnov test. The statistical significance for multiple group comparisons was determined via a one way ANOVA with Tukey’s post-hoc correction. Pairwise comparisons were performed using the Wilcoxon signed-rank test. ***P < 0.001, NS = Not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4502512&req=5

f1: Circulating sphingoid bases are increased in severe psoriasis patients.(a–d) Plasma levels of sphingoid bases are increased in severe psoriasis patients (n = 32) in comparison to healthy controls (n = 32) and mild psoriasis patients (n = 32). Each point represents an individual. A horizontal line shows the mean value for the group. (e–h) Levels of sphingoid bases are not affected by anti-TNF-α treatment in severe psoriasis patients (n = 16). Connected dots represent one individual. Normality was assessed by the Kolmogorov-Smirnov test. The statistical significance for multiple group comparisons was determined via a one way ANOVA with Tukey’s post-hoc correction. Pairwise comparisons were performed using the Wilcoxon signed-rank test. ***P < 0.001, NS = Not significant.
Mentions: Using ultra performance liquid chromatography—tandem mass spectrometry (UPLC-MS/MS), we quantified the sphingolipid levels in the plasma of patients with mild (n = 32) or severe psoriasis (n = 32) and healthy donors (n = 32) (Table 1). In addition, levels of circulating sphingolipids were determined in 16 of the severe psoriasis patients after 12 weeks of treatment with the anti-TNF-α drug Etanercept. Sphingolipids are discussed in terms of the lipid class (e.g, hexosylceramides) and the associated fatty acid chain (e.g., palmitic acid). The fatty acid nomenclature depends upon the length of the alkyl chain and degree of unsaturation. For example, lauric acid contains a 12 carbon saturated alkyl chain (C12:0) and nervonic acid possesses a 24 carbon alkyl chain with a single double bond (C24:1). Because of their high abundance in plasma, our analysis focused on the NS class of sphingolipids. In addition, NS is one of only two sphingomyelin classes that can produce ceramides by hydrolysis in the stratum corneum. Our analysis included extensive coverage of the sphingolipid pathway (30 species in total were quantified), consisting of a range of compounds including sphingomyelins, ceramides, hexosylceramides, lactosylceramides and dihydroceramides with varying fatty acid chain lengths (Supplementary Table 1). The analysis also included free phosphorylated and non-phosphorylated NS sphingoid bases (sphingosine, sphinganine, S1P and sphinganine-1-phosphate [Spa1P]). Supplementary Figure 1 provides an overview of sphingolipid metabolism. Circulating levels of sphingosine, S1P, sphinganine and Spa1P were significantly elevated (P < 0.001) in severe psoriasis patients compared with healthy controls and mild psoriasis groups. There were no significant differences between the healthy individuals and patients with mild psoriasis (Fig. 1a–d).

Bottom Line: Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin.In addition, the effects of anti-TNF-α treatment were determined.The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry 2, Karolinska Institutet, SE-17177, Stockholm, Sweden.

ABSTRACT
Sphingolipids are bioactive molecules with a putative role in inflammation. Alterations in sphingolipids, in particular ceramides, have been consistently observed in psoriatic skin. Herein, we quantified the circulating sphingolipid profile in individuals with mild or severe psoriasis as well as healthy controls. In addition, the effects of anti-TNF-α treatment were determined. Levels of sphingoid bases, including sphingosine-1-phosphate (S1P), increased in severe (P < 0.001; n = 32), but not in mild (n = 32), psoriasis relative to healthy controls (n = 32). These alterations were not reversed in severe patients (n = 16) after anti-TNF-α treatment despite significant improvement in psoriasis lesions. Circulating levels of sphingomyelins and ceramides shifted in a fatty acid chain length-dependent manner. These alterations were also observed in psoriasis skin lesions and were associated with changes in mRNA levels of ceramide synthases. The lack of S1P response to treatment may have pathobiological implications due to its close relation to the vascular and immune systems. In particular, increased levels of sphingolipids and especially S1P in severe psoriasis patients requiring biological treatment may potentially be associated with cardiovascular comorbidities. The fact that shifts in S1P levels were not ameliorated by anti-TNF-α treatment, despite improvements in the skin lesions, further supports targeting S1P receptors as therapy for severe psoriasis.

No MeSH data available.


Related in: MedlinePlus