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Keywords:

  • atherosclerosis;
  • psoriasis;
  • regulatory T cells;
  • T-helper 1 cells;
  • T-helper 17 cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Abstract:  Psoriasis and atherosclerosis are diseases in which effector T lymphocytes such as Helper T cells type 1 (Th1) and 17 (Th17) play integral roles in disease pathogenesis and progression. Regulatory T cells (Treg) also exert clinically important anti-inflammatory effects that are pathologically altered in psoriasis and atherosclerosis. We review the immunological pathways involving Th1, Th17 and Treg cells that are common to psoriasis and atherosclerosis. These shared pathways provide the basis for mechanisms that may explain the epidemiologic observation that patients with psoriasis have an increased risk of heart disease. Improved understanding of these pathways will guide future experiments and may lead to the development of therapeutics that prevent or treat cardiovascular complications in patients with psoriasis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Psoriasis and atherosclerosis share many similar underlying inflammatory mechanisms. In psoriasis, local elaboration of tumor necrosis factor-alpha (TNF-α) initiates a cascade of adaptive and innate immune cell differentiation, keratinocyte proliferation and development of psoriatic plaques. In atherosclerosis, inflammatory cells accumulate at sites of endothelial injury, contribute to atherosclerotic plaque, and mediate plaque instability and eventual myocardial infarction (1). Although other immune cell types including NK cells and B cells contribute to development of both psoriasis and atherosclerosis (2–5), the central role of T-cell subtypes in directing immune responses and the availability of therapies that modulate T-cell activation make these cell types an important area of mechanistic focus.

Patients with psoriasis have a high prevalence of co-morbid risk factors including insulin resistance, obesity and hypertension, which may increase their risk for developing cardiovascular disease (6,7). A number of epidemiologic studies have also suggested that patients with psoriasis have an increased risk of myocardial infarction independent of other established risk factors (8–11), but this finding remains controversial (12–14). Increased understanding of common immunological mechanisms linking psoriasis and atherosclerosis will help refine future studies in this area.

This viewpoint synthesises the currently known T-helper 1 (Th1), T-helper 17 (Th17) and regulatory T (Treg)-cell mechanisms underlying psoriasis and atherosclerosis. Based on these common mechanisms, we propose future areas of investigation to further define common T-cell pathways underlying psoriasis and atherosclerosis.

Th 1 in the pathogenesis of psoriasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Activation of the innate immune system initiates an inflammatory cascade in psoriasis that includes differentiation of T cells to a Th1 phenotype. Recent evidence also suggests that hematopoietic progenitors in patients with psoriasis may be biased towards a Th1 phenotype (15). Psoriasis is considered a prototypical Th1 response whereby Th1 cells activate macrophages, neutrophils and CD8+ cytotoxic T lymphocytes (16). In psoriasis plaques, key Th1 cytokines – interferon- γ (IFN-γ), interleukin (IL)-2 and TNF-α– activate keratinocytes and stimulate the production of inflammatory cytokines (TNF-α, IL-1β and IL-6), chemokines (chemokine ligand 8 through 11 and 20) and antimicrobial peptides (17). These mediators influence the inflammatory infiltrate and perpetuate the disease cycle.

Migration of T cells from systemic circulation to the dermis requires up-regulation of adhesion molecules. Endothelial cells in the cutaneous microvasculature up-regulate a variety of adhesion molecules during inflammatory states. E-selectin is upregulated in the dermal microvasculature of inflamed cutaneous tissue and serves as the endothelial ligand for the cutaneous lymphocyte antigen (CLA) on memory T cells. Keratinocytes in psoriatic plaques express intercellular adhesion molecule-1 (ICAM-1) (18,19), which is typically absent in the skin of patients without psoriasis. T-cell binding to these endothelial adhesion molecules increases T-cell migration into the dermis.

Recruitment of Th1 cells from the dermis to the epidermis is a key event in research models of psoriasis (20). T-cell localisation to the tissue begins with rolling on the vessel wall, which is mediated primarily by selectins and very late antigen-4 (VLA-4). VLA-4 (α4β1-integrin, CD49d/CD29), is a heterodimeric adhesion receptor that binds to the vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1. Following transient rolling, leucocytes attach firmly to the endothelium through adhesion of β2-integrins, thereby committing themselves to leave the circulation. To achieve dermal localisation, the extravasated lymphocytes bind primarily to β1-integrins and transmigrate through the dermal extracellular matrix. Other molecules that aid in dermal localisation of cutaneous lymphocytes include CD44, a hyaluronate receptor and LFA-1 (21).

Th 1 in the pathogenesis of atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Increased circulating levels of Th1 cytokines such as TNF-α lead to endothelial dysfunction and T-cell extravasation from the vascular compartment to sites of atherosclerotic plaque (22). Activated dendritic cells in atherosclerotic plaques express IL-12. IL-12 activates the transcription factor signal transducer and activator of transcription 4 (STAT4) and the Th1 transcription factor T-box expressed in T cells (T-bet). Activation of STAT4 and T-bet leads to upregulation of IFN-γ, which promotes a Th1 response. When combined with IL-18, IL-12 can also induce greater expression of IFN-γ, leading to further Th1-cell differentiation.

Although both Th1 and Th2 responses can contribute to atherogenesis (23), multiple lines of observational evidence support a predominance of the Th1 response (24–26). Compared with healthy controls, patients with stable angina and acute coronary syndromes (ACS) have increased STAT4 transcriptional levels in CD4+ T lymphocytes (27). T-cell clones from most atherosclerotic plaques produce IFN-γ (24), a finding that is also supported by immunochemistry studies (25,26). IL-12 is expressed in significant quantities in atherosclerotic lesions (28). When investigators studied a comprehensive panel of cytokines elaborated in atheromas, they confirmed the predominance of Th1 cells in human atherosclerotic plaques (26). Thus, these observational data suggest that Th1 responses in atherosclerotic plaques are necessary not only for initiation but also for perpetuation of plaque inflammation and instability (29). Further functional analysis will be necessary to confirm these observational findings.

Shared Th1 responses in psoriasis and atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

The activation of a Th1 response by IL-12 is well recognised in psoriasis and atherosclerosis. Thus, both the initiating events (such as activated dendritic cells and IL-12) as well as the downstream expression of cytokines are common to the pathogenesis of both conditions. TNF-α inhibitors such as infliximab, adalimumab and etanercept have significantly advanced the treatment of psoriasis, but it is unclear whether such drugs reduce the incidence of heart disease. Because TNF-α is a potent stimulant of endothelial dysfunction, TNF-α inhibitors or other agents such as fumaric acid may normalise endothelial function and thereby limit atherosclerotic progression (30). One approach to test this hypothesis would be to test the levels of circulating biomakers of endothelial function (such as soluble VCAM or E-selectin) (31), or to measure flow-mediated dilation in patients with psoriasis before and after initiation of anti- TNF-α therapies. A decrease in circulating markers of endothelial dysfunction or increase in flow-mediated dilation with anti- TNF-α therapies could support a mechanistic link between the Th1 pathways mediating psoriasis and atherosclerosis.

Th17 in the pathogenesis of psoriasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Interleukin-17 was described in the mid-1990s as a proinflammatory cytokine produced by Th17 cells, a population of Th cells distinct from Th1 or Th2 (32). Th17 cells also produce IL-6, IL-21, IL-22 and TNF. These cytokines are involved in epithelial immunosurveillance and neutrophil recruitment. Since their discovery, researchers have found that Th17 cells play an important role in several inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis and atherosclerosis (32,33).

Th17 and its products play an important role in the pathogenesis of psoriasis. A combination of cytokines initiates the differentiation of naïve helper T cells to the Th17 phenotype. Mouse studies show that transforming growth factor-β (TGF-β) in combination with IL-6 induce Th17 differentiation (34). Some evidence suggests that IL-1β, IL-23 or IL-6 alone may be each adequate to stimulate Th17 polarisation (34). Once the Th17 phenotype is achieved, IL-23 maintains a cellular Th17-polarisation (35).

Th17 cells secrete IL-17 and IL-22, which activate keratinocytes to proliferate and to produce a host of proteins that perpetuate the inflammatory cycle (17,36,37). One of these proteins, LL37-cathelicidin, forms complexes with self-DNA that is released by dying keratinocytes. These complexes, unlike naked DNA, are able to enter plasmacytoid dendritic cells (pDCs) by endocytosis, where they are recognised by intracellular Toll-like receptors 7 and 9. These pDCs are then able to present self-antigens to the T cells in the skin and lymph nodes, which enhances T-cell activation and proliferation (38). Upregulation of local endothelial cell adhesion molecules allows these T cells to migrate into the inflamed skin (38). IL-17 additionally activates DC maturation and induces macrophages to produce more pro-inflammatory cytokines (39).

IL-17 may also be involved in angiogenesis that occurs in psoriasis. In vitro studies have shown that IL-17 induces endothelial cell migration and cord formation (40). In vivo, IL-17 stimulates neovascularisation in rat corneas (40). When added to cultured fibroblasts, IL-17 alone significantly increased production of inflammatory and angiogenic factors including monocyte chemoattractant protein-1 (MCP-1), KC (the murine analogue of IL-8), nitric oxide and vascular endothelial growth factor (VEGF). Together, IL-17 and TNF-α synergistically increased fibroblast secretion of KC and had additive effects on production of VEGF (41).

Translational and clinical evidence also supports the role of Th17 in psoriasis pathogenesis (39,42–44). For example, IL-17 is undetectable in normal skin, and biological therapy that inhibits Th17 pathways results in reduced expression of IL-17 and IL-23 and improved disease outcomes (39,42,43). IL-17 serum levels correlated with the psoriasis area and severity index (PASI) (44).

Th17 in the pathogenesis of atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Th17 cells and their cytokines also factor prominently in atherosclerosis. Cheng et al. (45) showed that patients with ACS have significantly higher circulating levels of Th17 and IL-17 than patients with stable angina or non-cardiac chest pain. In a separate study, serum levels of IL-17 in patients with ACS positively correlated with levels of high-sensitivity C-reactive protein and IL-6, both of which have been shown to independently predict increased risk of myocardial infarction (46–48). Additionally, inhibition of IL-17 in mice has been shown to significantly reduce the size of atherosclerotic lesions (49).

Expression of the IL-17 receptor on endothelial cells and vascular smooth muscle cells makes arteries particularly susceptible to pro-inflammatory feedback loops involving IL-17 (50). An inciting event, such as endothelial injury, results in the local release of pro-inflammatory cytokines. These cytokines transform a naïve T cell into a Th17 phenotype and signal additional changes that allow it to traverse endothelial cell tight junctions. Once inside the arterial wall, Th17 secretes IL-17, which stimulates local endothelial cells, smooth muscle cells and macrophages to secrete various pro-inflammatory cytokines (including TNF-α), chemokines, adhesion molecules and other proinflammatory factors (50,51). TNF-α and IL-17 then synergistically up-regulate transcription of other cytokines, such as IL-6 (52,53). Meanwhile, the endothelial and smooth muscle cells create a positive feedback loop by producing more IL-17 (50). These inflammatory cascades cause increased local oxidative stress and make the plaque less stable. Intimal macrophages phagocytise oxidised low-density lipoprotein (LDL) and become foam cells in an increasingly necrotic atherosclerotic core. Substances like matrix metalloproteinase (MMP) degrade collagen and other extracellular matrix components, causing destabilisation, and eventual rupture, of the plaque’s fibrous cap (54).

Although Th1 cells are approximately 10 times more prevalent in atherosclerotic plaques than Th17 cells, Th17 cells exert a robust synergistic effect on atherogenesis (33). Plasma levels of IL-17 and IFN-γ are undetectable in healthy patients, but they are elevated and positively correlated in patients with coronary artery disease, indicating that both the Th17 and Th1 pathways are upregulated in atherosclerosis (33). In cell culture, IL-17 and IFN-γ synergistically increase production of pro-inflammatory factors such as IL-6, IL-8, chemokines, complement 5a and soluble ICAM-1 (33). IL-17R deficient mice show a 46% reduction in aortic plaque size compared with controls as well as a significant decrease in IL-6 production, supporting the pro-inflammatory, pro-atherogenic role of IL-17 (55).

Shared Th17 responses in psoriasis and atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Shared inflammatory mediators in the Th17 response may partially account for the observed association at a population level between psoriasis and myocardial infarction. Experimental evidence and biomarker studies suggesting a link between IL-17 and plaque instability in atherosclerosis could explain the apparent increased risk of myocardial infarction observed in patients with psoriasis. Measuring circulating levels of IL-17 amongst patients with psoriasis and coronary artery disease, as compared with patients with coronary artery disease but not psoriasis, could identify the additive contribution of IL-17 to the risk of myocardial infarction. Additionally, measuring levels of IL-17 in patients with psoriasis may identify subsets of patients with psoriasis at increased risk of subsequent myocardial infarction.

Regulatory T cells in psoriasis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Regulatory T (Treg) cells are a subtype of T lymphocytes whose primary function is to inhibit T-cell activation and proliferation. Treg cells do not proliferate in response to polyclonal stimulation; rather, they exert T-cell suppressive functions through cell–cell contact and production of anti-inflammatory cytokines, such as IL-10 and TGF-β (56–60). TGF-β has also been shown to promote naïve helper T-cell differentiation into Treg cells in the presence of other co-stimulatory molecules (56–60). Because TGF-β is a potent growth inhibitor of keratinocytes, researchers have hypothesised that reduced TGF-β signalling may contribute to keratinocyte proliferation in psoriasis. For example, a significant reduction in TGF-β receptors in psoriatic epidermis has been reported (61,62). However, the precise role of TGF-β in psoriasis has not been defined, and ongoing mice studies using keratin 5 promoter-controlled overexpression of latent human TGF-β1 continue to help elucidate our understanding (63,64). Interestingly, increased TGF-β levels have been found in the serum and epidermis of patients with psoriasis (65) and serum levels of TGF-β appear to correlate with disease activity (66,67). Therefore, it is difficult to determine whether increased TGF-β1 levels have a causal relationship in psoriasis pathogenesis or if it represents a consequence of psoriasis.

Cooper et al. was amongst the first to investigate the role Treg cells in psoriasis (68). They found that, in the peripheral blood, there were no significant differences in the proportion of Treg cells between patients with psoriasis and normal volunteers (68). However, whereas Treg cells exhibited nearly complete inhibition of T-effector cells in normal volunteers, the inhibitory function of Treg cells was markedly reduced in patients with psoriasis (69). Furthermore, psoriatic Treg cells also exhibited reduced inhibition of T-effector cells from normal volunteers in a cross-over experiment (69).

Regulatory T cells in atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Similar to their anti-inflammatory functions in psoriasis, Treg cells play an important role in mitigating atherogenesis. Antigenic stimulation of Treg cells leads to production of TGF-β and IL-10. Experiments in mice have shown that IL-10 and TGF-β decrease plaque formation (70,71). Specifically, TGF-β has pleiotropic effects on endothelial cells, smooth muscle cells and immune cells, and an increased concentration of TGF-β has been associated with reduced inflammation and atherosclerosis (72). It is postulated that Treg cells inhibit atherosclerosis via TGF-β signalling (73). Specifically, if host T-cells fail to respond to TGF-β signalling, Treg cells do not appear to influence atherosclerotic lesion size or inflammatory phenotype (73). Therefore, it appears that TGF-β is critical for the atheroprotective effects of Treg cells (73). Transgenic experiments also revealed that IL-10 exerts substantially anti-atherosclerotic effects (70,74,75); however, the cellular targets and regulation of this signalling are yet to be elucidated.

Whilst Foxp3+ Treg cells are absent in normal human arteries, they can be observed in the intima of diseased arteries during all stages of a developing atherosclerotic plaque (76). Patients with ACS exhibit a decreased number of Treg cells as well as reduced Treg cell function (77). Investigators showed that statin therapy increases circulating Treg cells in vivo, which suggests that statins may modulate atherosclerosis by facilitating conversion of Th cells to a Treg cell phenotype (78). Furthermore, administration of Treg cells to mice results in decreased Th1 responses, reduced plaque volume, decreased accumulation of inflammatory cells within the plaque and preservation of fibrous cap components (29).

Shared regulatory T-cell responses in psoriasis and atherosclerosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Treg cells play an important role in the pathogenesis of both psoriasis and atherosclerosis (Fig. 1). In psoriasis, the inhibitory function of Treg was significantly reduced compared with controls (69). Similarly, patients with coronary artery disease possess a reduced number and functions of Treg cells (77). In atherosclerosis, Treg cells can serve as a source or target of TGF-β, the primary T-cell-specific inhibitor of Th1 and Th2 responses. Identifying novel targets to enhance Treg cell activity or the circulating number of Treg cells has the potential to treat psoriasis and limit atherosclerotic plaque progression.

image

Figure 1.  Shared immunological mechanisms between psoriasis and atherosclerosis. In psoriasis (left panel), myeloid dendritic cells secrete IL-12 and IL-23, which results in T-cell differentiation into Th1 and Th17 subtypes. Th1 cells in psoriatic plaques secrete tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), leading to keratinocyte activation, expression of adhesion molecules including intercellular adhesion molecule 1 (ICAM-1), and keratinocyte proliferation. Th17 cells secrete IL-17 and IL-22, which promote both keratinocyte proliferation and intraplaque angiogenesis. Decreased levels of Treg cells lead to altered levels of transforming growth factor-beta, which promotes further Th1 and Th17 cell activation. In atherosclerosis (right panel), endothelial activation at sites of nascent arterial plaque promotes monocyte and lymphocyte extravasation and subsequent macrophage and dendritic cell elaboration of IL-12 and IL-23. Differentiated Th1 cells promote further atherosclerotic plaque growth, whilst Th17 cells promote intraplaque neoangiogensis and intraplaque haemorrhage. Increased levels of intraplaque IL-17 may lead to further weakening of the fibrous cap, with subsequent plaque rupture and myocardial infarction.

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Can we kill two birds with one stone?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

Shared immunological mechanisms in the development of psoriasis and atherosclerosis present potential common therapeutic targets. Targeting Th1 and Th17 responses and/or restoring a healthy ratio between Treg and effector T-cell activity may prove effective treatments for both psoriasis and atherosclerosis. Current systemic therapies, such as biologics for psoriasis, target these inflammatory pathways, but further translational and clinical research is necessary to examine their effect on cardiovascular outcomes in patients with psoriasis.

Several studies have investigated the effect of treatments for psoriasis on circulating biomarkers that may reflect risk of cardiovascular disease. Boehncke et al. (30) showed that treatment of psoriasis with fumaric acid ester reduces circulating CRP and increased the vascular protective cytokine adiponectin; these changes may reflect improvements in endothelial cell function. Similar results were observed with continuous systemic therapies for psoriasis (79). Serial studies of patients undergoing PUVA and UV-B therapy have shown reductions in circulating IL-17, IL-23 and TNF-α, suggesting possible interactions between inflammation in psoriatic plaque and risk of systemic atherosclerosis (80,81). These studies will need to be confirmed with hard endpoints of cardiovascular outcomes. For example, a large retrospective study suggested that methotrexate, especially in lower doses, may reduce the incidence of vascular disease in patients with psoriasis (82).

Interrupting circulating levels of Th17 cytokines may also target both psoriasis and cardiovascular risk. Retinoic acid, a Vitamin A derivative, was found to promote TGF-β-related Treg differentiation and inhibit the IL-6-driven induction of the Th17 phenotype. Thus, restoration of physiological Treg/Th17 activity ratio may be one mechanism by which retinoic acid exerts its efficacy in treating psoriasis (83,84). These possible beneficial effects may need to be balanced against possible adverse effects of serum lipid levels (85). Systemic treatments with TNF-α antagonists and monoclonal antibodies against IL12/23 reduced the detectable level of IL-17 (39,42–44). From these findings, we postulate that the associated reduction in IL-17 may limit the development of atherosclerosis, as IL-17 inhibition in mice has led to significant reduction in atherosclerotic plaque size (49).

As novel biologics agents are evaluated for psoriasis, researchers may consider assessing their effects on atherosclerosis. For example, ustekinumab, a recently approved monoclonal antibody for the treatment of psoriasis, mitigates the Th1 and Th17 responses induced by IL-12 and IL-23, respectively (44). Given that Th1- and Th17- mediated mechanisms have been identified as key players in the development of atherosclerosis, further studies are necessary to examine short-term and long-term cardiovascular effects from this treatment. Whilst agents that target the Th17 pathway may be expected to have beneficial cardiovascular effects based on proposed mechanisms of action, clinical data must be carefully examined to evaluate potential adverse cardiovascular effects (86). Results from integrated analyses of ustekinumab data from phase II and III studies on cardiovascular safety was published in February 2011. Through up to 3 years, the incidence of major adverse cardiovascular events (MACE) was 0.44 per 100 patient-years (95% CI: 0.27, 0.67) for those treated with ustekinumab. Compared with the general US and psoriasis populations, the standardised incidence ratios for ustekinumab-treated patients suggested no increased risk of MI or stroke (87).

Briakinumab is another human monoclonal antibody against p40 subunit of IL-12 and IL-23. Published phase II data show that briakinumab is efficacious in treating moderate-to-severe psoriasis (88). To date, whilst phase III data have only been published in abstract form at professional conferences (89–91), no phase III data on safety of briakinumab have been published in full-length in peer-reviewed journals. An ongoing multi-centred open-label extension study for long-term assessment of briakinumab’s safety showed that MACE occurred at an incidence rate of 0.60 events per 100 person years (95% CI: 0.35, 0.94) and that rate of MACE was higher in patients with two or greater cardiovascular risks compared with patients with fewer cardiovascular risks. The manufacturer withdrew its US and European applications for briakinumab for additional studies on efficacy and safety (92).

Tocilizumab is an anti-IL-6 monoclonal antibody currently used for the treatment of rheumatoid arthritis. Elevated serum IL-6 appears to be associated with greater psoriasis severity (39), and it is a predictive factor for ACS (44). Elevated serum IL-6 from psoriatic inflammation may alter the balance between Th17 and Treg cells systemically, thereby predisposing patients with psoriasis to develop atherosclerosis. Thus, although no anti-IL6 agents are current approved for psoriasis treatment, their mechanism of action can be postulated to be useful in the treatment of both psoriasis and atherosclerosis. Other possible future agents that interrupt immune cell adhesion, such as heparin derivatives (93), may target pathways common to both psoriasis and cardiovascular disease.

Cardiovascular treatment aimed at preventing and treating atherosclerosis may also be beneficial in reducing psoriasis disease severity. For example, researchers showed that statin therapy increases circulating Treg cells in vivo, which suggests that the statins may modulate atherosclerosis by facilitating conversion of undifferentiated T cells to Treg (78). Limited clinical studies have examined the effect of statins on psoriasis. Vasiuk et al. (94) examined the efficacy and safety of atorvastatin in the treatment of severe psoriasis in 63 patients. Compared with the control group, patients with psoriasis taking atorvastatin experienced an improvement in psoriasis disease severity and a significant decrease in serum TNF and hs-CRP levels (94). Strong evidence supports the role of statins in reducing development of atherosclerosis, and preliminary evidence for their beneficial role in psoriasis deserves further investigation with larger clinical studies. Because endothelial dysfunction is an obligate step in atherosclerotic progression, further investigation into the link between psoriasis, T-cell activation and endothelial dysfunction may also prove helpful in treating both psoriasis and atherosclerosis (79).

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References

This viewpoint article discussed the currently known common immunological mechanisms underlying ‘two plaques’– psoriasis plaque and atherosclerotic plaque. With increasing epidemiologic evidence showing a significant association between these two diseases that is unexplained by traditional cardiac risk factors, investigators have begun to search for common immunological mechanisms underlying these two conditions. Emerging in vitro and in vivo data have suggested commonalities in Th1, Th17 and Treg responses between these two diseases. These investigations have both clinical and translational relevance, as clinicians and investigators strive to determine the link between the two diseases as well as effective treatment modalities. Based on these shared immunological mechanisms, further studies will be necessary to examine whether systemic agents that modify immunological responses in psoriasis may have additional effects on cardiovascular outcomes.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Th 1 in the pathogenesis of psoriasis
  5. Th 1 in the pathogenesis of atherosclerosis
  6. Shared Th1 responses in psoriasis and atherosclerosis
  7. Th17 in the pathogenesis of psoriasis
  8. Th17 in the pathogenesis of atherosclerosis
  9. Shared Th17 responses in psoriasis and atherosclerosis
  10. Regulatory T cells in psoriasis
  11. Regulatory T cells in atherosclerosis
  12. Shared regulatory T-cell responses in psoriasis and atherosclerosis
  13. Can we kill two birds with one stone?
  14. Conclusion
  15. Acknowledgements
  16. Funding source
  17. Conflict of interest
  18. References