Bioactive Lipid Mediator Profiles in Human Psoriasis Skin and Blood

Abstract

Psoriasis is a chronic immune-mediated disease that represents a unique model for investigating inflammation at local and systemic levels. Bioactive lipid mediators (LMs) are potent compounds reported to play a role in the development and resolution of inflammation. Currently, it is not known to what extent these LMs are involved in psoriasis pathophysiology and related metabolic dysfunction. Here, we use targeted and untargeted liquid chromatography-tandem mass spectrometry approaches to quantify LMs in skin and peripheral blood from psoriasis patients and compared them with those of healthy individuals. Lesional psoriasis skin was abundant in arachidonic acid metabolites, as 8-, 12- and 15-hydroxyeicosatetraenoic acid, compared with adjacent nonlesional and skin from healthy individuals. Additionally, a linoleic acid-derived LM, 13-hydroxyoctadecadienoic acid, was significantly increased compared with healthy skin (607.9 ng/g vs. 5.4 ng/g, P = 0.001). These psoriasis skin differences were accompanied by plasma decreases in antioxidant markers, including glutathione, and impaired lipolysis characterized by lower concentrations of primary and secondary bile acids. In conclusion, our study shows that psoriasis skin and blood have disease-specific phenotype profiles of bioactive LMs represented by omega-6 fatty acid-oxidized derivatives. These findings provide insights into psoriasis pathophysiology that could potentially contribute to new biomarkers and therapeutics.

Conflict of interest statement

CONFLICT OF INTEREST

The authors state no conflict of interest. NNM is a full-time US Government employee and receives research grants to the National Heart, Lung, and Blood Institute from AbbVie, Janssen, Celgene, and Novartis.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Heatmap of plasma biochemicals identified in psoriasis patients

Heatmap represents plasma levels of different fatty acids based on the metabolomics scan of 30 healthy individuals and 60 psoriasis patients. Color plot is based on the mean levels of the metabolite within the studied cohort and described as scaled intensity.

Figure 2. Representative biochemical profile of psoriatic and healthy plasma

Fold change of key metabolites, (a) 9- and 13-HODE, (b) lauroylcarnitine, (c) glycerol, (d) 5-oxoproline, (e) γ-glutamylglutamine, (f) methionine, (g) cysteine, (h) glycochenodeoxycholate, (i) taurodeoxycholate, (j) adenosine 5′-diphosphate, (k) 7-β-hydroxycholesterol, (l) xanthosine, (m) sphingosine-1-phosphate, (n) N-stearoyl taurine, and (o) serotonin, were identified after ultra-high performance liquid chromatography and tandem mass spectrometry combined with gas chromatography/mass spectrometry (see Materials and Methods section for details). Values represent the mean ± standard error of the mean. n = 60 for the psoriasis group, n = 30 for the healthy group. P-values were derived from the Welch t test. P < 0.05 was considered statistically significant.

Figure 3. Representative biochemical profile of psoriatic and healthy skin

Lipid mediators, (a, c, e) free forms and (b, d, f) total (sum of free and esterified), derived from AA and LA were identified by liquid chromatography and tandem mass spectrometry (see Materials and Methods section for details). Results are expressed as ng/g tissue. Values represent the median (interquartile range). n = 8 for the psoriasis group, n = 7 for the healthy group. P-values were derived from the Mann-Whitney test. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 when comparing lesional with healthy skin data. DiHOME, dihydroxyoctadecenoate; EpOME, epoxyoctadecamonoenoic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; oxoODE, oxooctadecadienoic acid.

Figure 4. Explanatory outline of oxylipin biosynthesis and its estimated function in psoriasis

Cutaneous fatty acids and bioactive lipid mediators contribute to the formation and maintenance of the epidermal barrier. These have been implicated in various inflammatory skin conditions, including psoriasis. Pathways involving lipid mediators in maintaining normal homeostasis in the skin and alteration in fatty acid composition and metabolism in psoriatic skin are shown. LA and ALA are the main sources of omega-6 and omega-3 fatty acids, respectively, which in humans are derived from the diet. Thus, dietary imbalance in polyunsaturated fatty acids (PUFAs) leads to an alteration in the metabolism of their derivatives, AA, EPA, and DHA. Furthermore, the metabolism of PUFA is a complex process involving several enzymes of desaturation, elongation, and β-oxidation, resulting in production of respective bioactive derivatives, as shown in sectiona1 and a2. (b) In membrane phospholipids, LA gives rise to AA, which in turn leads to an increase in COX and LOX enzyme production of AA-derived eicosanoids and a decrease in EPA/DHA-derived metabolites. This process culminates in class switching of lipid mediators, finally leading to an increase in proinflammatory cytokines and a decrease in pro-resolution lipid mediators, specialized pro-resolving mediators. As a consequence, PPARα gene expression is down-regulated, and NF-κβ gene expression is up-regulated, manifesting in corresponding protein synthesis. Psoriasis modulates eicosanoid synthesis, which is important in the formation of the lipid mediators that include specialized pro-resolving mediators, resolvins, and lipoxins. The rapidly proliferating psoriasis epidermis generates an excessive amount of ambiguously functioning mediators such as hydroxy fatty acids, proinflammatory 9-HODE and anti-inflammatory 13-HODE, which can be taken up by the circulating LDL. Additional uptake of HODEs from the skin, along with circulating LA, further increases oxidation and formation of oxidized LDL, which promotes atherogenesis. Other potential pathways of interest include those of sphingolipids and endocannabinoids metabolism, which also are modulated in psoriasis. AA, arachidonic acid; ALA, α-linolenic acid; COX, cyclooxygenase; CYP450, cytochrome P450; DHA, docosahexaenoic acid; DiHOME, dihydroxyoctadecenoate; EC, endocannabinoid; EDP, epoxydocosapentaenoic acid; EET, epoxide eicosatrienoic acid; EPA, eicosapentaenoic acid; EpETE, epoxyeicosatetraenoic acid; EpOME, epoxyoctadecamonoenoic acid; FA, fatty acid; HDHA, hydroxydocosahexaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HpETE, hydroperoxyeicosatetraenoic acid; LA, linoleic acid; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LOP, lipoprotein lipase; LOX, lipoxygenase; LT, leukotriene; Mar, maresin; oxLDL, oxidized low-density lipoprotein; oxoODE, oxooctadecadienoic acid; PD/PDx, protectin; PG, prostaglandin; PLA2, phospholipase A2; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptor; Rv, resolvin; SPH, sphingolipid; TG, triglyceride.

Figure 4. Explanatory outline of oxylipin biosynthesis and its estimated function in psoriasis

Cutaneous fatty acids and bioactive lipid mediators contribute to the formation and maintenance of the epidermal barrier. These have been implicated in various inflammatory skin conditions, including psoriasis. Pathways involving lipid mediators in maintaining normal homeostasis in the skin and alteration in fatty acid composition and metabolism in psoriatic skin are shown. LA and ALA are the main sources of omega-6 and omega-3 fatty acids, respectively, which in humans are derived from the diet. Thus, dietary imbalance in polyunsaturated fatty acids (PUFAs) leads to an alteration in the metabolism of their derivatives, AA, EPA, and DHA. Furthermore, the metabolism of PUFA is a complex process involving several enzymes of desaturation, elongation, and β-oxidation, resulting in production of respective bioactive derivatives, as shown in sectiona1 and a2. (b) In membrane phospholipids, LA gives rise to AA, which in turn leads to an increase in COX and LOX enzyme production of AA-derived eicosanoids and a decrease in EPA/DHA-derived metabolites. This process culminates in class switching of lipid mediators, finally leading to an increase in proinflammatory cytokines and a decrease in pro-resolution lipid mediators, specialized pro-resolving mediators. As a consequence, PPARα gene expression is down-regulated, and NF-κβ gene expression is up-regulated, manifesting in corresponding protein synthesis. Psoriasis modulates eicosanoid synthesis, which is important in the formation of the lipid mediators that include specialized pro-resolving mediators, resolvins, and lipoxins. The rapidly proliferating psoriasis epidermis generates an excessive amount of ambiguously functioning mediators such as hydroxy fatty acids, proinflammatory 9-HODE and anti-inflammatory 13-HODE, which can be taken up by the circulating LDL. Additional uptake of HODEs from the skin, along with circulating LA, further increases oxidation and formation of oxidized LDL, which promotes atherogenesis. Other potential pathways of interest include those of sphingolipids and endocannabinoids metabolism, which also are modulated in psoriasis. AA, arachidonic acid; ALA, α-linolenic acid; COX, cyclooxygenase; CYP450, cytochrome P450; DHA, docosahexaenoic acid; DiHOME, dihydroxyoctadecenoate; EC, endocannabinoid; EDP, epoxydocosapentaenoic acid; EET, epoxide eicosatrienoic acid; EPA, eicosapentaenoic acid; EpETE, epoxyeicosatetraenoic acid; EpOME, epoxyoctadecamonoenoic acid; FA, fatty acid; HDHA, hydroxydocosahexaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HpETE, hydroperoxyeicosatetraenoic acid; LA, linoleic acid; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LOP, lipoprotein lipase; LOX, lipoxygenase; LT, leukotriene; Mar, maresin; oxLDL, oxidized low-density lipoprotein; oxoODE, oxooctadecadienoic acid; PD/PDx, protectin; PG, prostaglandin; PLA2, phospholipase A2; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptor; Rv, resolvin; SPH, sphingolipid; TG, triglyceride.