Oxidised lipids and their role in the immunopathology of psoriasis

Abstract

Dyslipidaemia is known to be one of the major contributory factors in atherosclerosis and cardiovascular disorders. In particular, increased circulating low-density lipoprotein (LDL) and accumulation in the vascular bed is thought to have damaging effects. Abnormal lipid profiles in patients with psoriasis have also been identified and it is hypothesised that a similar pathogenesis underlies the two conditions. In particular, the oxidative modification of the LDL particle (oxLDL) is thought to promote inflammation. This thesis therefore aims to investigate whether lipid accumulation and oxidation influences inflammation and vascular function.

The inflammatory events occurring in psoriasis were modelled in this thesis using in vitro assays for angiogenesis, endothelial cell migration, inflammatory cell recruitment under flow and immune cell proliferation. Human umbilical vein endothelial cells (HUVECs) were used as a model endothelium to study the effects of oxidised lipids on vascular function. In order to analyse the lipid contribution to inflammation, serum was depleted of lipids and compared to serum with a full lipid profile. The addition of lipids such as ox-/LDL was evaluated in complete and delipidated serum.

This investigation showed that in the absence of serum lipids, endothelial tube formation was significantly impaired, in addition to endothelial cell migration being inhibited. The proliferation of peripheral blood mononuclear cells (PBMCs) was also abrogated in the absence of serum lipids. Serum lipid depletion did not, however, have any effect on the ability of TNFα- or IFNg-stimulated endothelial cells to recruit leukocytes under shear stress. The addition of oxLDL had biphasic effects on endothelial responses by significantly enhancing migration at lower concentrations of 5µg/mL, yet significantly inhibiting this response at higher concentrations of 100µg/mL. In the recruitment assay, higher concentrations of oxLDL were able to increase the basal recruitment of neutrophils to the endothelial monolayer whereas lower concentrations had no effect on recruitment. Native LDL had no significant effect on these parameters at equivalent concentrations. OxLDL-induced endothelial migration was inhibited by the addition of a sphingosine kinase inhibitor and a blockade of S1P1 on endothelial cells. OxLDL induced migration was not affected by the inhibition of PAF-R. Flow cytometry was used to assess the expression of oxLDL receptors on HUVEC, showing no expression of LOX-1 but slight increases in CD36 expression, although not reaching statistical significance.

These data indicate that serum lipids are key in supporting in the angiogenic response, likely by affecting endothelial cell migration, in addition to having an important role in the maintenance of immune cell proliferation. Oxidised lipids have also been shown to have biphasic effects on inflammatory processes, dependent on concentration. These results also highlight the critical role for S1P in oxLDL-induced endothelial cell migration, with the blockade of sphingosine kinase and S1P1 effectively inhibiting these vascular responses. This thesis highlights the importance of the oxidation of LDL and subsequent oxLDL concentration on regulating inflammation. Further understanding in the mechanisms of oxLDL-induced inflammation may provide a therapeutic target in psoriasis and other related inflammatory conditions.

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Identifiers

ORCID for Timothy Millar: orcid.org/0000-0002-4539-2445

ORCID for Michael Ardern-Jones: orcid.org/0000-0003-1466-2016

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