• IL-10
• IL-6
• cytokines
• diabetes
• microparticles
• non-surgical periodontal treatment
• periodontitis
• systemic inflammation

• atherosclerosis
• extracellular vesicles
• long non-coding RNA
• microRNA
• psoriasis
• rheumatoid arthritis
• type 2 diabetes mellitus

• Humans
• Blood Platelets/immunology
• Autoimmune Diseases/immunology
• Rheumatic Diseases/immunology
• Inflammation/immunology
• Chronic Disease

• Arthritis
• Atherosclerosis
• Biomarkers
• Glycocalyx
• Heart disease risk factors

• Humans
• Cardiovascular Diseases
• Endothelium, Vascular
• Glycocalyx/metabolism
• Glycocalyx/pathology
• Risk Factors
• Atherosclerosis
• Arthritis/pathology
• Inflammation/pathology
• Heart Disease Risk Factors

• cardiovascular disease
• cytokines
• endothelial cell
• leukocyte
• platelet
• psoriasis

• Humans
• Cardiovascular Diseases/epidemiology
• Inflammation
• Thrombosis
• Psoriasis/epidemiology
• Comorbidity
• Platelet Activation

• National Natural Science Foundation of China
• Natural Science Foundation of Chongqing

• atherosclerosis
• cardiovascular risk
• circulating biomarkers
• endothelial dysfunction
• psoriasis
• vascular biomarkers

• Biologic agents
• Inflammatory cytokines
• Psoriasis
• Psoriasis-related comorbidities

• PAK4
• TNF
• apoptosis
• endothelial microparticle
• inflammation

• Inflammation
• Platelets
• Psoriasis
• Thrombosis

Psoriasis is one of the most common immune-mediated inflammatory diseases of the skin. The identification of the pivotal molecular mechanisms responsible for the disease pathogenesis may lead to the development of novel therapeutic options. The present study aimed to identify pivotal differentially expressed genes (DEGs) and methylated DEGs in psoriasis. The raw data from gene microarrays were obtained from the Gene Expression Omnibus database. The data were processed using packages in Bioconductor. In total, 352 upregulated and 137 downregulated DEGs were identified. The upregulated DEGs were primarily enriched in the 'innate immune defense' response and the 'cell cycle'. The down-regulated DEGs were primarily enriched in 'cell adhesion' and 'tight junction pathways'. A total of 95 methylated DEGs were identified, which were significantly enriched in the 'interleukin (IL)-17 signaling pathway' and the 'response to interferon'. Based on a comprehensive evaluation of all algorithms in cytoHubba, the key epigenetic-associated hub genes (S100A9, SELL, FCGR3B, MMP9, S100A7, IL7R, IRF7, CCR7, IFI44, CXCL1 and LCN2) were screened out. In order to further validate these genes, the present study constructed a model of imiquimod (IMQ)-induced psoriasiform dermatitis using mice. The levels of these hub genes were increased in the IMQ group. The knockdown of methylation-regulating enzyme ten-eleven translocation (TET) 2 expression in mice attenuated the expression levels of S100A9, SELL, IL7R, MMP9, CXCL1 and LCN2. Furthermore, the hydroxymethylated level of S100A9 was highly expressed in the IMQ group and was significantly decreased by TET2 deficiency in mice. On the whole, using an integrative system bioinformatics approach, the present study identified a series of characteristic enrichment pathways and key genes that may serve as potential biomarkers in psoriasis.

• psoriasis
• bioinformatics analysis
• differentially expressed genes
• differentially methylated genes
• S100A9

Endothelial cells (ECs) line the luminal surface of blood vessels and have an active role in the recruitment of leukocytes, including immune cell activation. Regulatory T cells (Tregs) are immune suppressor cells that maintain peripheral tolerance and must interact with the endothelium as they traffic into tissue. We hypothesized that human ECs could modulate Tregs and their suppressor function. Cocultures of CD4⁺ T cells with human umbilical vein ECs (HUVECs) or dermal microvascular ECs (HDMECs) were conducted and analyzed for activation and proliferation after 72 and 120 h using flow cytometry. In monocyte-depleted cultures, human ECs were found to support CD4⁺ T cell proliferation in the presence of external mitogens phytohemagglutinin or anti-CD3/28 antibodies (aCD3/28). Activation was shown by CD25 expression in these cells that also transiently expressed the Treg transcription factor FOXP3. HUVECs supported the specific concurrent proliferation of both effector T cells and Tregs when cocultured with aCD3/28. Purified Tregs were also functionally activated by prior coculture with EC to suppress effector T (Teff) cell proliferation. Both direct coculture and indirect coculture of EC and Treg showed activation of the Treg suppressive phenotype. However, whereas HUVEC showed enhancement of suppression by both mechanisms, HDMEC only supported Treg suppressive activity via the contact-independent mechanism. In the contact-independent cultures, the soluble mediators IL-6, GM-CSF, or G-CSF released from ECs following interferon-γ activation were not responsible for the enhanced Treg suppressor function. Following direct coculture, Treg expression of inhibitory receptors PD-1 and OX40 was elevated while activated EC expressed the counter ligands programmed death ligand (PD-L)1 and PD-L2. Therefore, human ECs have a role in supporting T cell proliferation and increasing Treg suppressor function. This ability of EC to enhance Treg function could offer novel targets to boost Treg activity during inflammatory disorders.

• CD4+ T cells
• cell–cell interaction
• endothelial cells
• immune regulation
• regulatory T cells

Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment.

• atherosclerosis
• cardiovascular disease
• cerebrovascular disease
• diabetes mellitus
• dyslipidemia
• hypertension
• metabolic syndrome
• obesity
• psoriasis
• systemic inflammation

• Cardiovascular Diseases/epidemiology
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/prevention & control
• Comorbidity
• Female
• Humans
• Male
• Methotrexate/therapeutic use
• Psoriasis/complications
• Psoriasis/drug therapy
• Risk Factors

• Cardiovascular disease
• Cytokines
• Endothelial function
• Glucocorticoids
• Plasma microparticles

Psoriasis is associated with atherosclerosis, in which circulating microparticles play an important role. In severe psoriasis, there was an increase of endothelial- and platelet- microparticles which could be decreased by anti-TNFα. However, whether anti-IL-12/23 treatment would decrease the level of microparticles remains unknown. Our study showed that, despite the clinical improvement of psoriasis after IL-12/13 blockage, the increased levels of circulating CD41a and CD31 microparticles were unchanged after anti-IL-12/23. This result suggested that anti-IL12/23 treatment may not alter the development of cardiovascular disease in patients with psoriasis.

The deterioration of endothelial structure plays a very important role in the development of vascular diseases. It is believed that endothelial dysfunction starts in the early stage of kidney disease and is a risk factor of an unfavorable cardiovascular prognosis. Because a direct assessment of biological states in endothelial cells is not applicable, the measurement of endothelial microparticles (EMPs) detached from endothelium during activation or apoptosis is thought to be a marker of early vascular disease and endothelial dysfunction in children with chronic kidney disease (CKD). Few studies have shown increased circulating EMPs and its relationship with cardiovascular risk factors in patients with CKD. MPs contain membrane proteins and cytosolic material derived from the cell from which they originate. EMPs having CD144, CD 146, CD31⁺/CD41^-, CD51 and CD105 may be used to evaluate the vascular endothelial cell damage and determine asymptomatic patients who might be at higher risk of developing cardiovascular disease in CKD and renal transplant.

• Endothelial dysfunction
• Endothelial microparticles
• Kidney transplantation
• Chronic kidney disease

Psoriasis patients exhibit an increased risk of atherothrombotic events, including myocardial infarction and stroke. Clinical evidence suggests that psoriasis patients with early onset and more severe disease have the highest risk for these co-morbidities, perhaps due to the extent of body surface involvement, subsequent levels of systemic inflammation, or chronicity of disease. We sought to determine whether acute or chronic skin-specific inflammation was sufficient to promote thrombosis.

We used two experimental mouse models of skin-specific inflammation generated in either an acute (topical Aldara application onto wild-type C57Bl/6 mice for 5 days) or chronic (a genetically engineered K5-IL-17C mouse model of psoriasiform skin inflammation) manner. Arterial thrombosis was induced using carotid artery photochemical injury (Rose Bengal-green light laser) and carotid artery diameters were measured post-clot formation. We also examined measures of clot formation including prothrombin (PT) and activated partial thromboplastin time (aPTT). Skin inflammation was examined histologically and we profiled plasma-derived lipids. The number of skin-draining lymph-node (SDLN) and splenic derived CD11b⁺Ly6C^high pro-inflammatory monocytes and CD11b⁺Ly6G⁺ neutrophils was quantified using multi-color flow cytometry.

Mice treated with topical Aldara for 5 days had similar carotid artery thrombotic occlusion times to mice treated with vehicle cream (32.2 ± 3.0 vs. 31.4 ± 2.5 min, p = 0.97); in contrast, K5-IL-17C mice had accelerated occlusion times compared to littermate controls (15.7 ± 2.1 vs. 26.5 ± 3.5 min, p < 0.01) while carotid artery diameters were similar between all mice. Acanthosis, a surrogate measure of inflammation, was increased in both Aldara-treated and K5-IL-17C mice compared to their respective controls. Monocytosis, defined as elevated SDLN and/or splenic CD11b⁺Ly6C^high cells, was significantly increased in both Aldara-treated (SDLN: 3.8-fold, p = 0.02; spleen: 2.0-fold, p < 0.01) and K5-IL-17C (SDLN: 3.4-fold, p = 0.02; spleen: 3.5-fold, p < 0.01) animals compared to controls while neutrophilia, defined as elevated SDLN and/or splenic CD11b⁺Ly6G⁺ cells, was significantly increased in only the chronic K5-IL-17C model (SDLN: 11.6-fold, p = 0.02; spleen: 11.3-fold, p < 0.01). Plasma-derived lipid levels, PT and aPTT times showed no difference between the Aldara-treated mice or the K5-IL-17C mice and their respective controls.

Chronic, but not acute, skin-specific inflammation was associated with faster arterial thrombotic occlusion. Increased numbers of splenic and SDLN monocytes were observed in both acute and chronic skin-specific inflammation, however, increased splenic and SDLN neutrophils were observed only in the chronic skin-specific inflammation model. Understanding the cellular response to skin-specific inflammation may provide insights into the cellular participants mediating the pathophysiology of major adverse cardiovascular events associated with psoriasis.

The online version of this article (doi:10.1186/s12967-015-0738-z) contains supplementary material, which is available to authorized users.

• cardiovascular disease
• clinical studies
• microparticles
• microvesicles