The lipoxygenase‐hepoxilin pathway is activated in cutaneous plaque lesions of psoriasis

Abstract

There is increasing evidence that hepoxilins are novel inflammatory mediators. In vitro studies have shown that hepoxilins cause the mobilization of intracellular calcium in human neutrophils, induce plasma leakage, and potently stimulate the chemotaxis of human neutrophils. In vivo, the hepoxilin pathway is activated in conditions with inflammation, for example, pathogen infection, psoriasis, and arthritis, and hepoxilins promote inflammatory hyperalgesia and allodynia. 1 The "hepox" comes from hydroxy-epoxy, and the "ilin" comes from hepoxilins' activity as an insulin secretagogue (albeit an activity whose physiological significance remains unconfirmed). AbstractPsoriasis is a common skin disorder that is characterized by hyperkeratosis, epidermal hyperplasia, T-cell and neutrophil recruitment, and changes in the vascular endothelial system. The several upregulated variable lipid mediators, including the eicosanoids, in psoriatic keratinocytes were described previously, although some results were contradictory. Since hepoxilin is less stable than other eicosanoids such as hydroxyeicosatetraenoic acid (HETE), the measurement of hepoxilin is difficult. In this study, to clarify the relationship between hepoxilin/hepoxilin-related fatty acid derivatives and psoriasis vulgaris, we evaluated the amount of production of lipid mediators including hepoxilins in skin tissues of patients with psoriasis vulgaris in comparison with normal controls by high-performance liquid chromatography/mass spectrometry. Most of the hepoxilins and related lipids evaluated in this study tended to be more abundant in the lesional skin from the psoriasis patient group (PPG) than in the skin from controls. Interestingly, 12R-HETE was markedly higher in the skin samples from the PPG. In addition, the lipids produced in the lipoxygenase pathway, including hepoxilin, were elevated in the skin lesions of the PPG compared with those of normal controls, whereas the lipids produced in the cyclooxygenase pathway were decreased in the skin lesions from the PPG. Our results suggest that an imbalance between the lipoxygenase and cyclooxygenase pathways may contribute to psoriatic pathomechanisms. K E Y W O R D S cyclooxygenase, hepoxilin, lipoxygenase, psoriasis vulgaris, psoriatic arthritis How to cite this article: Takeichi T, Kinoshita F, Tanaka H, et al. The lipoxygenase-hepoxilin pathway is activated in cutaneous plaque lesions of psoriasis. J Cutan Immunol Allergy. 2019;2:15-24. https://doi.

Lipidomic and transcriptional analysis of the linoleoyl-omega-hydroxyceramide biosynthetic pathway in human psoriatic lesions

“…Almost all the known genes involved in either generation of long chain ceramides, or their oxygenation were significantly upregulated in psoriatic lesions indicating that this pathway is highly active (Figure 9). This significantly expands on previous observations that 12R-LOX is upregulated in both lesional and non-lesional skin in psoriasis, showing the entire pathway is affected (21,22,39,40).…”

Metabolomics Studies in Psoriatic Disease: A Review

“…Generally, psoriatic disease-related metabolomics studies aim to identify metabolic markers that can be used for Ps and/or PsA diagnosis. While a few studies have examined the metabolite profiles of patients with autoimmune diseases (ADs) [9,10], or immunemediated inflammatory diseases (IMIDs) with no emphasis on Ps or PsA specifically [11], the majority of studies included in this review sought to identify metabolites that were associated with Ps by investigating Ps patients in comparison to healthy volunteers [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Other studies focused on identifying metabolite profiles in Ps patients and correlating them with different measurements of disease activity [13,19,22,28,32,33].…”

“…Most studies included in our literature search were non-hypothesis driven and therefore employed an untargeted metabolomics approach [12,[14][15][16][19][20][21][22][23]25,26,[31][32][33]36,41,42]. However, there were several studies that analyzed specific metabolites using a targeted metabolomics approach [9,10,13,18,24,27,28,30,39,40]. Fewer studies exploited both ap-proaches to analyze different classes of metabolites [17,29,35], while a couple studies initially performed an untargeted discovery study followed by validation of the results in a targeted way [11,34].…”

“…Obtaining tissue samples is an invasive process but offers researchers insight into tissue directly implicated in the disease being studied and tissue specific metabolites involved. Thus, there were several studies that investigated the skin metabolome of Ps patients [22][23][24][25][26][27].…”

“…Solid-liquid extraction (SLE) is another liquid-partitioning method very similar to LLE that isolates analytes from solid and semi-solid matrices. A couple of studies utilized this method to extract metabolites from skin samples [25,27]. Protein precipitation (PPt) is another widely used sample preparation method for biological fluids that can sometimes be categorized as an LLE method since it requires usually the addition of cold solvent to allow the precipitation of proteins from the sample, which are then effectively removed, leaving only the metabolites [44].…”