Since a substantial amount of data accumulates in the past of this issue, we provide a brief insight into the most common inflammation-related and non-inflammatory factors involved in accelerated atherogenesis in Ps and PsA. As previously mentioned, Ps and atherosclerosis have a similar immune innate and adaptive pathogenic hallmark and an active crosstalk between “traditional” or “non-traditional” (Figure 1) .
4.1.1. Innate immunity
Toll-like receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) trigger receptor-mediated events, including cytokine-mediated inflammation, are involved in atherosclerosis , Ps, and other pathologies . TLR expression is positively correlated with plasma tumor necrosis factor-alpha (TNF-α) levels . Cytokine-triggered TLRs activation is known to modulate major pathological processes, including inflammation, angiogenesis, tissue remodeling, and fibrosis. Although joints are the most obvious inflammation sites in PsA, proinflammatory cytokines, most likely TNF-α and interleukin 6 (IL-6), are released in blood circulation and act on distant organs (immune system, adipose tissue, liver, hematopoietic tissue, skeletal muscle, glands, and endothelium). These effects are linked to systemic inflammation and lead to a proatherogenic profile. Cytokines orchestrate endothelial adhesiveness, matrix metalloproteinases (MMPs) activation, reactive oxygen species (ROS) production, C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) release .
Indeed, atherogenic lipid alterations, oxidative stress abnormalities, vascular injury repair failure, arterial stiffness, insulin resistance induction, endothelial dysfunction, hypercoagulable state, homocysteine elevation, and pathogenic T cell up-regulation could all be attributed in part to the proinflammatory actions of cytokines. Common inflammatory mechanisms in Ps and atherosclerosis may be related to other factors by the high number of overlapping molecules, including cytokines [interleukins (IFN-α, IL-2, IL-6, IL-10, IL-13, IL-15, IL-17, IL-18, IL-20, and IL-23)], interferon alpha (IFN-α), Oncostatin M, (TNF-α), chemokines [Fractalkine, growth-regulated oncogene (GRO) alpha], CCL-3(MIP-1α), CCL-4 (MIP-1α), CCL-11 (Eotaxin), IL-8, MCP-1, monokine induced by interferon gamma (MIG/CXCL9), adipokines (Resistin, Leptin, and PAI-1), adhesion molecules (ICAM/LFA-1(leukocyte function-associated antigen-1), CD154 (OX40L)/CD134 (OX40), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), and GCSF, co-stimulatory molecules (CD80, CD28, and CD40/CD40L), lymphocyte profile Th1/Th17 up-regulation, Treg down-regulation, CTL effect or activity, NK cells, natural killer T (NKT) cells, myeloid dendritic cells, plasmacytoid dendritic cells, monocytes/macrophages, mast cells and neutrophils, complement activation , TLR-mediated inflammation (TLR-2, TLR-4, and TLR-9) [27–29], and other important factors, such as CRP, endothelin-1, inducible nitric oxide synthase (iNOS), heat shock protein (HSP60, HSP65, and HSP70), matrix metalloproteinases (MMP-2 and MMP-9), and oxidized low-density lipoprotein (LDL) [45, 48, 49]. Some molecules listed before and other PsA-related serum cytokine patterns have been demonstrated by multiplex cytokine array systems in Norwegian PsA patients [50, 51]. Few of these cytokines previously mentioned [52, 53] and their pathogenic contribution at different stages in the pathobiology of atherothrombosis and PsA are not clear yet .
NK cells increase the susceptibility to PsA  and the inflammatory infiltrate in psoriatic skin lesions. Although more studies must be done, emerging evidence supports a role for NK cells in Ps. Inverse correlation exists between NK cell population and body mass index (BMI). Therefore, adipose immune cell phenotype and function may provide greater insight into cardio-metabolic pathophysiology in psoriasis [54, 55].
NKT cells are a heterogeneous subset of T cell lineage lymphocytes that bear NK cell molecules and T cell receptors, which recognize microbial glycolipids and their own endogenous mammalian lipids presented by the MHC I-like molecule (CD1d) and have been implicated in the pathogenesis of various autoimmune diseases including Ps. Due to the numerous functions of NKT cells that link innate and adaptive immunity, their role in Ps is complex and still elusive. ApoE and LDL receptors have been involved in antigen uptake for presentation to NKT cells  NKT cells may represent a potential new therapy for atherosclerosis .
Our knowledge of biologically active serum molecules and cells involved in the pathogenesis of both PsA and atherosclerosis is still not clear enough. Taken together, cytokines seem to play a pivotal role as the major link between PsA and atherosclerosis. Compiled data show that untreated PsA inflammation could produce damage to the CV system even before it affects the joints . Current evidence suggests that the pathway of inflammation in atherosclerosis culminates in altered concentrations of various markers in peripheral blood, including oxidative stress molecules [58–60] and markers of vascular inflammation like CRP , IL-6, ICAM-1, and MCP-1 .
184.108.40.206. Tumor necrosis factor-α
The pleiotropic cytokine TNF-α is among the most potent mediators of inflammation. Circulating T lymphocytes and monocyte-derived macrophages isolated from PsA patients produce increased amounts of TNF-α in comparison with macrophages isolated from healthy controls . Furthermore, levels of TNF-α in PsA patients are elevated in the synovial tissue and skin lesions and correlate with disease activity. TNF-α is a key regulator of vascular homoeostasis , leading to proatherogenic effects, lipid abnormalities, including high LDL cholesterol and low HDL cholesterol , hypercoagulable state via induction of cell surface expression of tissue factor (TF) on the endothelial wall and suppress anticoagulant activity via the thrombomodulin-activated protein C system . The majority of epidermal CTL and Th1 effector lymphocyte populations and molecules are elevated in Ps vulgaris lesions and in circulating blood in psoriatic patients . TNF-α also induces endothelial dysfunction including low nitric oxide availability and up-regulation of endothelial adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) [65, 66], a critical early step in atherogenesis. On the other hand, TNF-α blockade leads to a significant decrease in the levels of lipoprotein a (Lpa) homocysteine and an increase in apolipoprotein A-I (Apo A-I), triglyceride, and Apo-B concentration . Long-term use of TNF-α blocking agents interferes with TNF-α function reducing the high incidence of cardiovascular events and associated vascular complications in CV diseases . Taken together, the above-mentioned studies confirm a critical role for TNF-α in altering a number of well-studied putative vascular, thrombotic, and metabolic risk parameters (lipids and lipoproteins).
220.127.116.11. Interleukin 6
As an inflammatory cytokine, IL-6 regulates chemokine-directed leukocyte trafficking and directs transition from innate to adaptive immunity through the regulation of leukocyte activation, differentiation, and proliferation . During acute and chronic inflammatory response, macrophages release TNF-α in the presence of a great variety of stimuli, including atherogenic and poorly characterized arthritogenic factors. TNF-α action on macrophages triggers the release of more TNF-α and IL1-β, which stimulate endothelial cells to produce IL-6 and IL-8. IL-6 and their signaling events contribute to hepatic release of acute-phase reactants including CRP levels, atherosclerotic plaque development and destabilization [69, 70]. IL-6 may also contribute to atherosclerosis and arterial thrombosis by activating the production of tissue factor, fibrinogen and factor VIII; increasing endothelial cell adhesiveness and stimulating platelet production and aggregation . In addition, IL-6 is produced by smooth muscle cells (SMC) of many blood vessels and by adipocytes and, together with CRP and TNF-α, is involved in metabolic syndrome pathophysiology, insulin resistance  and coronary artery disease and the risk of MI [73–76], and cardiovascular mortality . In addition, IL-6 locally produced in the endothelium and in SMC is an important autocrine and paracrine regulator of SMC proliferation and migration. IL-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway activating STAT3-dependent anti-inflammatory signal transduction .
Numerous studies show a strong association between IL-6 and joint immune-mediated diseases. In the joint, macrophages and mast cells trigger a proinflammatory cascade in the presence of unknown stimuli, releasing great amounts of TNF-α, which induce the expression of IL-1 and IL-6. Mice deficient in mast cells are comparatively resistant in experimentally induced arthritis. In addition, it is a major promoter of bone resorption in pathological conditions . In particular, IL-6 has a pivotal role in synovitis, bone erosion, and in the systemic features of inflammation .
In Ps, most available evidence indicates that the pathogenic action of IL-6 is important. In fact, IL-6 co-localizes with CD45+ perivascular cells within lesional tissue and reverses the suppressive function of human T-regulatory cells .
The successful treatment of certain autoimmune conditions with the humanized antibody anti-IL-6 receptor (IL-6R) (Tocilizumb) has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 .
IL-6 may, in both cardiovascular and joint-diseases involving Th1/Th17 mechanisms, alter the balance between the effector and regulatory arms of the immune system and drive a proinflammatory phenotype reinforcing innate and adaptive immune-mediated positive feedback , potentiating the immune effector mechanism. In both arterial disease and Ps/PsA, IL-6 seems to be a critical mediator of long-term chronic inflammation and to have deleterious effect in the arterial wall and in the joint.
The family of endothelins (ET) includes three 21-aminoacid isoforms endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), which have endogenous pressor activity and are secreted by different tissues and cells. In addition, ET-1 is a vasoactive peptide that induces vasoconstriction, inflammation, and fibrosis and has mitogenic potential for SMC . In the skin, ET-1 participates in keratinocyte proliferation, neoangiogenesis, and chemotaxis. Its levels are elevated in psoriatic lesions and serum of patients with Ps . Synovial tissue and serum of patients with PsA all show strongly enhanced ET-1 receptor expression .
18.104.22.168. C-reactive protein
A considerable amount of evidence implicates C-reactive protein (CRP) as a predictive marker for future CV events and mortality in different settings, particularly under metabolic syndrome conditions in the general population [87, 88]; CRP has also been implicated as a direct partaker [7, 89, 90]. In addition, CRP stimulates the production of plaque destabilizing MMPs and MCP-1, a decrease in the activity of endothelial nitric oxide synthase (eNOS) and impairment in endothelium dependent vasodilation . In vitro, studies provide evidence for direct proatherogenic effects of CRP, including increased endothelial dysfunction . Baseline CRP levels were elevated in patients with Ps with and without psoriatic arthritis and Etanercept, a biologic TNF antagonist, treatment may reduce CRP levels in both groups .
Interestingly, in metabolic disorders associated with Ps/PsA, inflamed adipose tissue may enhance inflammatory proatherogenic status via adipokine production (leptin, adiponectin, and resistin) and cytokine (TNF-α and IL-6) secretion. Adipose tissue influences both natural and adaptive immunities and links inflammation, metabolic dysfunction, and cardiovascular disease .
22.214.171.124. Matrix metalloproteinases (MMPs)
MMPs are endoproteases with collagenase and/or gelatinase activity which exert deleterious effects on the endothelium integrity and collagen fibers, promoting atherosclerotic plaque destabilization and accelerating the process of atherothrombosis . MMP-1 serum levels and gene expression are elevated in PsA .
4.1.2. Adaptive immunity
As previously mentioned, Ps/PsA and atherosclerosis share certain common underlying pathogenic inflammatory mechanisms. Specifically, both are associated with Th1 and CTL (cytotoxic T lymphocyte) effector cell-mediated events in vivo , and are elevated in circulating blood . In contrast, the T-regulatory activity is reduced.
126.96.36.199. Cellular immune response
Myeloid dendritic cells can stimulate both memory and naive T cells, and are the most potent of all the antigen-presenting cells in normal and various pathophysiological conditions . In turn, activated T cells undergo firm adhesion and transendothelial migration to inflammatory focus. Extravasation is orchestrated by the combined action of cellular adhesion receptors and chemotactic factors in a wide variety of cardiovascular and autoimmune disorders that involve inflammation.
The development and maintenance of psoriatic plaque are dependent on the participation of infiltrating T lymphocytes (CD4 and CD8) and local antigen-presenting cells (APCs) (Langerhans cells, myeloid, and plasmacytoid-DC). DCs are increased in psoriatic lesions and are critically involved in the induction of Th1 and Th17 cell proliferation, which, in turn, release IFN-γ and IL-17, respectively. Activated mDCs produce IL-23 [98, 99] and TNF-α. IL-23 stimulates the secretion of IL-22 by Th17 cells, which may be involved in epidermal hyperplasia . The effects of IL-17A-producing T-helper 17 (Th17) cells include suppressive effects of T-regulatory (Treg) subsets, which have also been implicated in both pathologies. The association of IL-17A with Ps and PsA has been extensively described [98, 99] and a growing body of evidence suggests that IL-17A might also be involved in atherosclerosis . IL-17 seems to have a modulatory role in atherosclerosis, but studies available show contrasting results, which could be attributed to different approaches and models. Coronary syndrome correlates with increased IL-17 levels . In addition, TNF-α and IL-17 synergistically up-regulate further cytokine transcription in both diseases, Ps and atherogenesis . These observations make IL-17A an interesting therapeutic target to modulate both PsA/Ps disease activity and atherosclerosis/cardiovascular risk. Obesity may play an important role by amplifying the inflammation of arthritis through the Th1/Th17 response . Limited evidence from Ps patients indicates that induction therapy with infliximab, with moderate to severe plaque Ps, led to decrease in clinical disease scores and circulating levels of Th17, Th1 cells, and associated TNF-α release .
T cell activation is under control from T-regulatory immune cell (Treg) activity via IL-10 and TGF-β [105–107]. Reduced numbers and/or activity of Treg cells may produce hyperactivity of Th1/Th17 subsets in both pathologies [21, 108, 109]. Ps and coronary artery disease patients show impaired inhibitory function of Treg [110, 111]. Serum and epidermal levels [105, 106] of TGF-β in Ps patients are associated with Ps disease severity [112, 113] and are diminished in low Ps . In atherosclerosis, high serum levels of TGF-β and IL-10 may inhibit plaque formation [114, 115] and plaque stabilization exerting protective effect due its inhibition of T cells .
188.8.131.52. Humoral immune response
Humoral response seems to protect rather than harm the host. Several lines of evidence support the hypothesis that humoral immunity protects patients against atherosclerosis. First, the injection of immunoglobulin preparations inhibits atherosclerosis. Second, spleen removal (a B-cell rich lymphoid organ) seems to deteriorate vascular disease condition. Third, oxidized LDL plus adjuvant immunization promote atheroprotection . Evidence so far indicates that atheroprotection is due to a T cell dependent B-cell-mediated mechanism, probably involving antibody dependent clearance of LDL and humoral dependent regulation of pathogenic T cell . This atheroprotective response must be confirmed in humans.
4.1.3. Genes related to the innate and adaptive immune system associated with psoriasis and atherogenesis
At least 10 chromosomal locus associated with psoriasis have been identified as PSORS (PSORS, psoriasis susceptibility) . Additionally, certain human leucocyte antigen (HLAs) are more common in psoriatic arthritis. HLA alleles that are specific for psoriatic arthritis are HLA-B27 and possibly HLA-B7, HLA-B38, and HLA-B39.
There is a strong association of psoriasis with the HLA-Cw6 allele, which increases 10–20 times the risk of psoriasis and is present in 90% of the patients with early onset psoriasis and in 50% of those with late onset psoriasis .
Some molecules of the innate immune system have an important influence on the pathophysiology of psoriasis, such as TLR2 and TLR4 play a key role in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes .
Additionally, the expression of TLR2 and TLR4 correlates with the degree and severity of coronary disease [120, 121] oxidized phospholipids stimulate the TLR signaling pathway to induce inflammatory cytokine secretion by macrophages and endothelial cells .
Anti-CD14 and anti-TLR antibodies significantly inhibit the binding of fluorescein-labeled LDL to monocytes and interfering with cytokine release . TNF-binding proteins are encoded by genes unrelated to PSORS, conferring susceptibility to psoriasis. Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) and tumor necrosis factor interacting protein 1 (TNIP1) are related to the inflammatory signal NF-κB, which regulates the release of TNF-α [124, 125].
TNFAIP3 promotes the survival of T-CD4 lymphocytes . Certain cytokine genes have been implicated with psoriasis, including IL-12, IL-23, IL-4/IL-13  conferring an increased risk of psoriatic arthritis .
These genes strengthened the assertion that psoriasis is an immune disorder, as these genes are linked to both the innate and adaptive immune response [129–131]. In summary, defects in these genes could amplify an inflammatory response by interfering with normal negative feedback of the NF-kB signal and therefore would link to psoriasis with other IMID and coronary pathology.