Oxidized Lipids and Lipoprotein Dysfunction in Psoriasis

Abstract

Background:

Psoriasis is a chronic immune-mediated inflammatory skin disease associated with increased development of metabolic abnormalities including obesity and dyslipidemia, as well as increased cardiovascular disease (CVD) risk. Shared pathophysiological mechanisms linking psoriasis to CVD include altered immune activation, elevated chronic systemic inflammation, and lipoprotein dysfunction characterized by oxidative damage to lipids and apolipoproteins.

Objective:

This review aims to provide evidence-based proof for existing relationships between psoriatic inflammation, lipid oxidation, and increased CVD risk.

Methods:

We included review articles and original research papers, published between 1980 and 2020, using the following key words: psoriasis, oxidized lipids, oxidation, dyslipidemia, and inflammation.

Results:

Systemic inflammation underlying psoriasis leads to increased skin accumulation of pro-inflammatory oxidized lipids, derived from the omega-6 fatty acids, along with counteracting anti-inflammatory lipid mediators, products of the omega-3 polyunsaturated fatty acids. Imbalance in these metabolites culminates in impaired inflammation resolution and results in multisystemic biological alterations. Sustained systemic inflammation results in excessive lipid oxidation, generating proatherogenic oxidized low- and high-density lipoproteins. Together, these pathophysiological mechanisms contribute to increased CVD risk associated with psoriasis disease.

Conclusion:

Available anti-inflammatory treatment showed promising clinical results in treating psoriasis, although further research is warranted on managing associated dyslipidemia and establishing novel cardiometabolic markers specific for both skin and vascular pathology.

Introduction

Psoriasis is a chronic inflammatory skin disease affecting multiple organ systems. It alters normal immune-mediated host responses,¹ anti-inflammatory,² and antioxidant functions,³ resulting in complex pathophysiological disturbances. Clinically, these alterations result in higher incidence of metabolic dysfunction, including diabetes mellitus⁴ and increased cardiovascular risk.⁵ Several studies have attempted to define underlying mechanisms linking chronic inflammation and cardiovascular complications.^6–8 Here, we aim to describe these associations from the perspective of oxidative damage, lipoprotein dysfunction, and their relationship to psoriasis.

Lipoprotein Dysfunction and Cardiovascular Disease in Psoriasis

Multiple clinical studies have shown that psoriasis disease severity associates with dyslipidemia,^9,10 including small, dense low-density lipoprotein (LDL) particles.¹¹ Interestingly, patients with psoriasis have a significant decrease in total cholesterol and LDL-cholesterol during the 5 years before onset,¹² associated with elevation in both lipid fractions, and triglycerides specifically, at the time of psoriasis development.¹³ Additionally, these changes correlate with oxidative status, supporting complexity of the involved mechanisms.¹⁴ It is believed that inflammation is the key driver of dyslipidemia in psoriasis, with circulating pro-inflammatory cytokines affecting high-density lipoprotein (HDL) composition, leading to decreased cholesterol efflux¹⁵ and altering levels of protective HDL proteins.¹⁶ The source of cytokines in psoriasis is mainly attributed to Th1 and Th17 cells with CD1b-autoreactive T cells shown to be involved in skin inflammation under hyperlipidemic conditions. It is well known that psoriasis is uniquely driven by cytokines such as interleukin-17 (IL-17) and IL-23.¹⁷ which is also shown recently to be affecting lipid trafficking.¹⁸ Indeed, T cells producing IL-17-mediated thickening of the collagenous matrix resulted in HDL blocking from efficient tissue transport in a model of experimental psoriasis. Moreover, HDL transit was restored by affecting CD4⁺ T cells, neutralizing IL-17, or preventing collagen crosslinking. Neutrophils are also related to HDL dysfunction and have been shown in both systemic lupus erythematosus¹⁹ and psoriasis²⁰ to drive early lipid accumulation responses.

This important immunologic component further tightens psoriasis disease with atherosclerosis pathophysiology. Recent views on coronary plaque disruption and atheroma progression outlines specific role of T cells and macrophages in these processes by generating matrix metalloproteinases (MMPs) and pro-inflammatory cytokines.²¹ Interestingly, MMPs genes, as well as collagenases, are expressed in psoriatic lesional skin and can be pharmacologically inhibited resulting in averted skin inflammation^22,23 and atherosclerosis.²⁴ The immunologic disturbance along with chronic inflammation might explain the observed abnormal changes in lipoproteins concentrations.

Persistent inflammation increases vascular risk effectively corrected with statin therapy²⁵; however, it remained unclear if the risk reduction was related to statin-induced LDL-cholesterol (LDL-C) decrease or lowering inflammation itself. Subsequent clinical studies revealed that anti-inflammatory therapy in those with history of myocardial infarction (MI) targeting the interleukin-1β innate immunity pathway led to a significantly lower rate of recurrent cardiovascular events independent of lipid-lowering effect.²⁶ Additionally, there was significantly lower risk of ischemic cardiovascular events following colchicine treatment²⁷ in those with very recent MI (eg, <3 months ago). In contrary, low-dose methotrexate failed to reduce pro-inflammatory markers and did not result in fewer cardiovascular events compared to placebo in those with history of MI.²⁸ Interestingly, results from these studies revealed that even with efficient inflammatory and lipid control, in statin-treated patients with very low LDL-C levels, residual cardiovascular risk failed to be predicted by HDL-cholesterol (HDL-C).²⁹ This controversy, along with the failure of drugs to elevate HDL-C to reduce cardiovascular disease (CVD) events,³⁰ raises a question on whether other measures of HDL besides its cholesterol content (HDL-C), might be more relevant and disease-specific including assessment of HDL function.³¹

The metabolic dysfunction accompanying psoriasis puts patients at higher risk for developing CVD. One of the largest prospective, populational studies reported high risk for MI³² and increased risk for developing atherosclerotic CVD and congestive heart failure.³³ Impaired glucose tolerance and associated obesity also contribute to the observed lipoprotein dysfunction in psoriasis pathogenesis. Indeed, it has been confirmed that visceral adiposity is associated with vascular inflammation in patients with psoriasis and can be reduced upon adequate treatment.³⁴ Moreover, epicardial fat³⁵ and perivascular fat attenuation index³⁶ may serve as additional markers capturing metabolic risk in patients with psoriasis. These observations delineate potential involvement of the impaired triglycerides metabolism along with overall alteration in the reverse-cholesterol transport (RCT) mechanisms (Figure 1), which need further exploration.

Figure 1.

Schematic outline of lipid oxidation and impaired lipoprotein metabolism in psoriasis. Psoriasis pathogenesis activates neutrophil-released myeloperoxidase (MPO) along with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in plasma, contributing to reactive oxygen species (ROS) and RAS GTPases overactivation in the endothelium. These signaling pathways ultimately lead to the phosphorylation of several transcription factors, such as nuclear factor-kappa B (NF-kB) in macrophages and endothelial cells. The imbalance in the antioxidant system provokes different functional activities of the pro-inflammatory genes. This pathological state developed in the vascular endothelium leads to NLRP3 inflammasome stimulation in macrophages and oxHDL modification of intracellular signaling via lectin-like oxLDL (LOX-I) receptor, which soluble form (sLOX-I) presents in circulation. Impaired paraoxonase I (PONI) enzyme function on high-density lipoprotein (HDL) and excessive inflammatory response lead to further lipid oxidation. Additionally, perivascular fat releases less adiponectin and more pro-inflammatory cytokines, such as IL-6, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-I (MCP-I). This cascade of pro-inflammatory and oxidation stimuli further activates synthesis of the lipoxygenase and cyclooxygenase pathways metabolites with generation of counteracting specialized proresolving mediators (SPMs). Sustaining oxidative and inflammatory state triggers excessive development of oxLDL and oxHDL, which results in lipoprotein transport alteration and impairment of the reverse-cholesterol transport (RCT) pathway (shown at left). This leads to insufficient apolipoprotein A-I (ApoA-I) interaction with the adenosine triphosphate-binding cassette transporter AI (ABCAI) transporter on macrophages and decreased cholesterol esterification by lecithin cholesterol acyltransferase (LCAT). This results in decreased return of cholesteryl esters to the liver either directly after interaction with hepatic scavenger receptor-BI (SR-BI) receptors or indirectly after transfer to LDL by cholesteryl ester transfer protein (CETP) and uptake by hepatic LDL receptors (LDL-R).

Oxidized Lipids and Lipoproteins in Psoriasis

Exacerbated oxidation in psoriatic skin was noted decades ago and was related to generation of hydroxy fatty acids from accumulated arachidonic (AA) and linoleic acids pathway markers in the rapidly proliferating psoriatic epidermis.^37,38 Interestingly, these oxidized fatty acids and corresponding epoxide forms have different lesional skin distributions and exhibit both anti- and pro-inflammatory properties.³⁹ Our group further elaborated on these earlier observations and found robust accumulation of specialized proresolving lipid mediators (SPMs), products of omega-3 fatty acids.⁴⁰ Lesional skin was abundant in anti-inflammatory bioactive lipids derived from docosahexaenoic acid (DHA), specifically resolvin D5 (RvD5) and protectin D1, as well as pro-inflammatory metabolites from AA. Confirming our results, RvD1 was found to decrease superoxide production and skin inflammation in a mouse model.⁴¹ These skin discrepancies, developed under disease state, support previous data that inflammation in psoriasis represents an active process of impaired resolution and oxidative imbalance.⁴²

Linoleic acid and AA are esterified into cholesterol esters, triacylglycerol, and phospholipids of lipoproteins, mainly in LDL⁴³ but also HDL⁴⁴ as well. Oxidized phospholipids (OxPLs) transported by oxidized LDL (oxLDL) facilitate interaction with endothelial cells through inflammasome induction, resulting in a cascade of multicomponent reactions leading to atherosclerosis propagation.⁴⁵ Although several studies have reported a context-dependent role of OxPLs emphasizing biased agonism of these lipids under disease-specific conditions,⁴⁶ phospholipid oxidation may also generate potent anti-inflammatory lipid mediators structurally similar to SPMs.⁴⁷ These divergent roles may in part explain why under excessive PL oxidation both LDL and HDL become significantly increased in patients with psoriasis.⁴⁸ Under conditions where LDL is completely saturated with OxPLs, HDL particles might serve as a sink for excess plasma OxPLs and participate in a context-dependent response that can be either pro- or anti-inflammatory. However, this hypothesis needs to be explored further in other disease-specific states.

Oxidized lipids that accumulate in psoriatic skin are not only produced locally but are also generated in LDL and HDL and then transported to skin via the blood circulation⁴⁹ (Figure 1). The major source of lipoprotein oxidative damage in the circulation is the oxidative enzyme myeloperoxidase (MPO), which is secreted into plasma by neutrophils and has been extensively characterized in conditions with evident inflammatory and atherosclerotic components.^50,51 Myeloperoxidase represents a universal oxidation mechanism for both LDL⁵² and HDL.⁵³

The role of oxLDL and its major apolipoprotein, apolipoprotein B (ApoB), in atherogenesis and inflammation is well established. OxLDL propagates endothelial damage and arterial plaque development and associates positively with negative CVD outcomes.⁵⁴ Oxidative stress damages HDL as well—not just lipids but also apolipoproteins such as apolipoprotein A-I, thereby reducing its key function of RCT.⁵⁵ High-density lipoprotein consists of many different kinds of particles, each carrying different protein cargos, several of which have antioxidant function. One major antioxidant protein is paraoxonase 1 (PON1), which is able to counteract damage by MPO-generated reactive oxygen species to both HDL and LDL. Paraoxonase 1, however, eventually suffers oxidative damage and becomes inactivated under severe oxidative stress, as well as inflammation.¹⁶ Low PON1 activity has been associated with worse prognosis for CVD and was found to be decreased in psoriasis.⁵⁶ Low PON1 activity caused by sustained inflammation and oxidation under pathological conditions,⁵⁷ as well as damage to lipids and other antioxidant and anti-inflammatory proteins on HDL particles, characterizes HDL as dysfunctional and contributes to the parameter called HDL inflammatory index.⁵⁸

Briefly, the balance between LDL oxidation and HDL’s capacity to prevent its further oxidation provide a mechanistic link between chronic inflammatory conditions, such as psoriasis and CVD.⁵⁹ An impaired antioxidant response in psoriasis affecting both young⁶⁰ and adult⁶¹ patients has been shown in recent clinical studies. High-density lipoprotein represents an important antioxidant function and its oxidative state and potential role is a matter of ongoing research. Psoriatic inflammation is shown to contribute to higher levels of oxLDL in both in vitro⁶² and clinical settings.⁴⁸ Recent work revealed that the lectin-like oxLDL receptor (LOX-1), which is expressed in endothelial cells, macrophages, and smooth muscle cells, binds multiple ligands, including oxLDL, oxHDL, oxidized HDL (oxHDL) C-reactive protein, and advanced glycated end products.^63,64

In addition to ligand binding and internalization, LOX-1 activation triggers intracellular signaling to induce proapoptotic, prooxidant, and pro-inflammatory pathways causing cell dysfunction associated with atherosclerosis, atherosclerotic plaque instability, and overall increase in CVD risk.^63,65 Complex vascular dysfunction triggered by LOX-1 also contributes to vascular calcification and arterial stiffness.⁶⁶

The serum-soluble form of LOX-1 (sLOX-1), which is the extracellular portion of LOX-1 produced by proteolytic shedding of the receptor, is thought to reflect membrane-bound intact receptor levels, and is elevated in acute coronary syndrome (ACS),⁶⁷ stable coronary artery disease,⁶⁸ and stroke⁶⁹ when compared with that of healthy volunteers, further suggesting a role in the atherosclerotic processes. Finally, using a “liquid biopsy” device to sample local biomolecule gradients across coronary atherosclerotic plaques, it was shown that the most abundant protein produced by human atherosclerotic lesions, but not normal vessels, was LOX-1.⁷⁰ In agreement with this observation, another study in patients with acute myocardial infarction (AMI) showed that sLOX-1 may reflect additive events related to plaque instability, as it was significantly increased in patients at the early phase of AMI. It was suggested that sLOX-1 may be a useful marker for AMI diagnosis and prognosis.⁷¹

In view of this observation, association between LOX-1 and coronary artery disease has been established in psoriasis.⁷² These data from preclinical and clinical observations strongly suggest that LOX-1 plays an important role in the potential mechanism by which oxidation-modified lipids (OMLs) increase inflammatory CVD risk and raise the possibility that blockade of LOX-1 may stabilize atherosclerosis by reducing residual inflammatory risk in post MI patients with ACS and in high inflammatory CVD risk patients such as those with PSO. Altogether, antioxidant system imbalance, systemic inflammation, and generation of oxidized bioactive lipoproteins sustain psoriasis disease and determine associated lipoprotein dysfunction (Figure 1).

Clinical Perspective

Despite extensive basic and clinical research, psoriasis remains one of the leading causes of disability in the United States.⁷³ This has stimulated development of novel therapeutic targets applied in psoriasis treatment with promising clinical outcomes. Most of the reported studies have targeted the main inflammatory and immune components related to IL-17A, IL-23, and tumor necrosis factor-alpha (TNF-α). Ixekizumab, an IL-17A inhibitor, showed promise in large 2 phase 3 trials⁷⁴ with similar effects for secukinumab in the STEPIn study.⁷⁵ The anti-IL-23 inhibitor, guselkumab, was also reported to be clinically effective in treating moderate to severe psoriasis.⁷⁶ Inhibiting TNF-α by novel biologics in chronic plaque psoriasis was also associated with significant clinical improvement.⁷⁷ Although treatment with adalimumab (anti-TNFα) reduced key markers of inflammation including GlycA and high-sensitivity C-reactive protein it was associated with an increase in ApoB-containing lipoproteins.⁷⁸ Furthermore, anti-TNF therapy has been shown to have negative weight effects. Inhibition of the IL-36 pathway in phase 1 treatment of generalized pustular psoriasis has also recently revealed promising significance.⁷⁹ Patients with psoriasis known to have a higher aortic vascular inflammation along with accelerated noncalcified coronary burden.⁸⁰ Recently, biologic therapy showed not only a cutaneous effect but also favorably modulated coronary plaque by reducing noncalcified plaque burden (NCB)⁸¹ and necrotic core.⁸² Decrease in NCB in the biologic-treated group was significant compared with slow plaque progression in nonbiologic treated. Adequate immunologic treatment improved lipid profile,⁸³ which was also effective in restoring HDL composition and function⁸⁴ in a small psoriasis study. However, the existed controversy of biologic treatment effects on lipoprotein metabolism needs further investigation. In our previous work, treatment of psoriasis with biologic therapy (anti-TNF, anti-IL-17, and anti-IL-12/23) was associated with significant reduction in OMLs, specifically oxHDL and oxLp(a) in a smaller subset of the cohort without altering lipid profile.⁴⁸ However, because of the limited number of patients involved in this analysis, these findings need further exploration in a large cohort study. As discussed above, circulating OMLs are known LOX-1 ligands, which responsible for CVD pathogenic processes such as inflammation-triggered atheroma growth and atherosclerotic plaque erosion and rupture.⁸⁵ Thus, inhibition of the sLOX-1 by a specific antibody might significantly abolish excessive lipid oxidation, mainly of OMLs, by decreasing inflammatory stimuli responses⁶⁷ and provide beneficial effects on dyslipidemia and coronary plaque progression associated with psoriasis. Indeed, recent clinical guidelines outlined psoriasis as a risk-enhancing feature in patients with borderline CVD risk, recommending moderate-intensity statin therapy in this cohort.⁸⁶

Statin remains the main lipid-lowering drug in patients with psoriasis determine their clinical effectiveness by immunomodulatory functions and inhibition of inflammatory responses beyond direct lipid-related effect.⁸⁷ However, common use of anti-inflammatory drugs such as methotrexate could have potentiate drugs interactions resulting in liver dysfunction and pharmacological incompetence.⁸⁸ Therefore, search for alternative drugs combinations is of great importance. For instance, the circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes the degradation of LDL receptors and results in the increased concentration of circulating LDL, has been shown to be elevated in psoriasis.⁸⁹ Whereas, suppressing PCSK9 can decrease the inflammatory reaction induced by imiquimod treatment and inhibit hyperproliferation of keratinocytes.⁹⁰ Although PCSK9 inhibitors considered as an effective tool for LDL-C lowering in high-risk patients,⁹¹ its clinical application in psoriasis cohort needs further investigation. Moreover, pharmacological targets specific for oxLDL function, as anti-sLOX-1 antibody, has clinical perspective in treating patients with chronic inflammatory conditions, such as atherosclerosis, psoriasis, and diabetes mellitus (NCT03654313).

Although the biologic therapy and other psoriasis treatments are effective, it has been reported that diet modification⁹² and addition of fish oils⁹³ to psoriasis treatment might have a favorable effect in controlling the disease state. Emerging use of polyunsaturated fatty acids (PUFAs) may be of clinical benefit; however, its role in psoriasis remains to be established.⁸⁸ As discussed earlier, omega-3 PUFAs significantly contribute to SPMs production by macrophages and neutrophils and increase its levels in circulation,⁹⁴ which helps to counteract persistent skin inflammation. There are number of controversial clinical trials investigating long-chain omega-3 PUFAs treatment in psoriasis⁹⁵ and patients with CVD.⁹⁶ Indeed, the most recent clinical study, REDUCE-IT, revealed significant CVD risk reduction under 4 g/d eicosapentaenoic acid (EPA) ethyl ester treatment,⁹⁷ whereas STRENGTH trial investigating 4 g/d of EPA and DHA mixture has been discontinued.⁹⁸ The existed differences between EPA and DHA are thought to be determined not only by different biological function of each PUFA but also relate to complex interactions established between these fatty acids and disease-specific humoral and cell environment.⁹⁹ In this context, EPA has favorable triglycerides lowering effect, whereas both EPA and DHA stimulate resolution by their corresponding pathways-derived bioactive lipid mediators.

Finally, antioxidant treatment targeting the antimitochondrial NLRP3 inflammasome pathway showed promise in managing atherosclerosis,¹⁰⁰ which can also potentially benefit psoriasis. A better understanding of lipoprotein oxidation and complex lipid interactions might help in managing psoriasis-associated lipoprotein dysfunction and overall psoriasis management.

Conclusion

Extensive work on psoriasis pathophysiology and pharmacological management revealed shared mechanisms with CVD, which specifically include anti-inflammatory and antioxidant systems imbalance. Recent characterization of psoriasis as a risk-enhancing feature in patients with borderline CVD risk is an effective achievement in clinical management of such patients with both skin and vascular complications. Thus, understanding currently approved psoriasis-specific treatment on lipid metabolism is of importance. Moreover, searching for new and determining existed pharmacological targets in psoriasis and associated CVD should be a matter of future research.