More and more evidence show that psoriasis increases the relative risk of atherosclerosis (about 25%) and is independent of risk factors, such as smoking, obesity, and hyperlipidemia (1). Patients with a course of psoriasis more than 8 years are more likely to develop atherosclerosis than non-psoriatic patients (2). Atherosclerosis is the pathological basis of psoriasis complicated with cardiovascular disease. Atherosclerosis and psoriasis have many overlapping inflammatory environmental factors, including local and systemic immune processes, inflammatory cytokines/chemokines, such as serum TNF-α, vascular endothelial growth factor, IL12, monocyte chemotaxis Protein 1, S100A8/A9 and significantly elevated IL17A, etc. (3).

Although psoriasis is considered as a risk factor for developing atherosclerosis, the exact mechanisms that explain the coexistence of these two disorders remain unclear. The IL23/IL17 axis could be the most fundamental pathway. Psoriasis and atherosclerosis have overlapping mechanisms in pathogenic pathways. In psoriasis, myeloid dendritic cells secrete IL12 and IL23, prompting T cells to differentiate into Th1 and Th17 cell subtypes; Th1 cells secrete TNF-α and IFN-γ, which promote the activation and proliferation of keratinocytes and the expression of adhesion molecules such as intercellular adhesion molecule 1 (4); Th17 cells secrete IL17 and IL22 to promote the proliferation of keratinocytes and angiogenesis in the lesion (5). In atherosclerosis, the activation of endothelial cells in the plaques of neonatal arteries promotes monocyte and lymphocyte overflow, and granulocyte-macrophage colony stimulating factor can promote the synthesis of IL12 and IL23 by macrophages and dendritic cells, reducing BCL2 and activating Th1 and Th17 responses (6). Th1 cells secrete TNF-α and IFN-γ to promote the further growth of atherosclerotic plaques, while Th17 cells secrete IL17 and IL22, and the release of reactive oxygen species increases, which promotes the formation of new blood vessels and intraplaque hemorrhage; Elevated IL17 levels in plaques may further weaken the fibrous caps in atherosclerotic plaques, leading to plaque rupture and myocardial infarction (1, 7).

The common transcription feature may provide new insights into the common pathogenesis of psoriasis and atherosclerosis. The purpose of this study is to identify hub genes related to the pathogenesis of psoriasis complicated with atherosclerosis. We analyzed two gene expression data sets (GSE30999 and GSE28829) downloaded from the GEO database. Comprehensive bioinformatics and enrichment analysis were used to determine the common DEGs and its functions of psoriasis and atherosclerosis. In addition, PPI network was constructed to analyze gene modules and identify hub genes by using STRING database and Cytoscape software. In the end, we identified 16 important hub genes, and we further analyzed the transcription factors of these genes and verified their expression. The hub genes identified here between psoriasis and atherosclerosis are expected to provide new insights into the biological mechanisms of these two diseases.

Insulin resistance induced by the inflammatory response in psoriasis can cause atherosclerosis. Research showed that a variety of inflammatory markers can be detected in the blood of patients with psoriasis, confirming that the body was in a systemic inflammatory state during the onset of psoriasis, which induced insulin resistance and reduced the release of vasodilator factors, then it provided an environmental basis for the formation of atherosclerotic plaques (19). Studies have shown that psoriasis is associated with atherosclerosis through dyslipidemia, including increased levels of total cholesterol, triglycerides, low-density lipoprotein, ultra-low-density lipoprotein and lipoprotein a, and the reduction of high-density lipoprotein and apolipoprotein B levels (20). Adipokines, including adiponectin, leptin, resistin, omentin, visfatin, chemoattractant and retinol binding protein 4, are considered to be risk factors for atherosclerosis. Among them, leptin, resistin, visfatin, chemoattractant and retinol binding protein 4 may be the common pathogenic factors of psoriasis and atherosclerosis. Adiponectin deficiency, leptin, visfatin and chemokine can induce and aggravate psoriasis by activating plasmacytoid dendritic cells and T cells (21, 22). It has been demonstrated that low-density granulocyte (LDG), which is a subset of neutrophils, is elevated in psoriasis and is related to skin disease severity and noncalcified coronary plaque burden. The main mechanism of neutrophil infiltration in patients with psoriasis complicated with atherosclerosis is that psoriasis LDGs may have a cytotoxic effect on endothelial cells, and in an inflammatory environment the adherence of LDG to platelets might be an important link between psoriasis skin disease severity and early atherogenesis (23).

Psoriasis and atherosclerosis might have overlapping pathogenic pathways. Inflammatory and immune regulatory pathways, such as IL23/IL17A pathways are linked to the pathogenesis of these two diseases. IL17A inhibitors are currently commonly used to treat psoriasis. The main purpose of our study is to identify the common DEGs in psoriasis and atherosclerosis. Thereby, revealing potential targets is to predict the therapeutic effect of biologics and treating psoriasis complicated with atherosclerosis.

We must acknowledge the genetic similarity between psoriasis and cardiovascular disease. Study found that single-nucleotide polymorphisms (SNPs) associated with increased risk for dyslipidemia (rs2247056, rs3177928, rs492602, and rs181362), increased blood pressure levels (rs805303, rs653178, and rs3184504), and increased risk for cardiovascular diseases (rs3184504) were associated with increased risk for psoriasis (24). The top three SNPs (rs2247056, rs3177928, and rs805303) were located in the HLA gene region. They also identified four non-HLA SNPs with evidence of shared genetic risk between psoriasis and cardiovascular and metabolic diseases: rs492603 in FUT2, rs181362 in UBE2L3, and rs653178 and rs3184504 near or in SH2B3 (24).

In this study, we identified 94 overlapping DEGs in both, of which 16 were hub genes, including LYN, CSF2RB, IL1RN, RAC2, CCL5, IRF8, C1QB, MMP9, PLEK, PTPRC, FYB, BCL2A1, LCP2, CD53, NCF2 and TLR2. GO and KEGG Pathway enrichment analysis revealed that these genes were significantly enriched in inflammatory and immune pathways. Chemokines and cytokines are jointly involved in the occurrence and development of these two inflammatory diseases, such as serum TNF-α, vascular endothelial growth factor, IL12, monocyte chemotaxis Protein 1, S100A8/A9 and significantly increased IL17A, which play a central role in the development of psoriasis and atherosclerosis. According to GO analysis, the lipopolysaccharide-mediated signaling pathway also play an important role in these two diseases. In psoriasis, lipopolysaccharide mediates nuclear transduction of NF-κB, then proinflammatory factors including TNF-α, IL6, and prostaglandin E (PGE) up- regulate in keratinocytes (25). In atherosclerosis, lipopolysaccharide, a Gram-negative endotoxin and an exogenous ligand for TLR4, can induce the activation of TLR4-MyD88-NF-κB signaling, followed by the release of atherosclerosis-related inflammatory factors such as TNF-α, IL1β, IL6, and MCP-1, leading to the development and progression of atherosclerosis (26). In addition, we found that 11 TFs may regulate the expression of these genes. By further verification, we found that four TFs are highly expressed in psoriatic lesions and atherosclerotic plaques, including IRF1, NFKBIA, REL, SPI1. They coordinately participated in the regulation of four hub genes (MMP9, CCL5, NCF2, and BCL2A1).

MMP9 is a member of MMPs, which 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 (27, 28). Visfatin, which is the common pathogenic factors of psoriasis and atherosclerosis, induces the increased expression of MMP9 in the carotid plaques in an indirect way (29). Studies have confirmed MMP9 is overexpressed in psoriatic neutrophils, and detected to be abundant in psoriatic skin lesions, especially adjacent to endovascular and perivascular tissues, indicating MMP9 may play a role in vascular remodeling in psoriasis. In psoriasis, MMP9 also significantly upregulates the mRNA levels of ICAM-1, IL1β and CXCL1 in vascular endothelial cells (VECs), which enables VECs interaction with more leukocytes (30). CCL5 is expressed and secreted by normal T cell. It is reported that CCL5 production by keratinocytes is increased in psoriatic skin lesions. CCL5 may contribute to the T helper-1-dominant infiltration in psoriatic lesions as well as CXC-chemokines. CCL5 also recruits macrophages. T helper-1 cells or macrophages infiltrating into psoriatic lesions in turn may produce CCL5 and proinflammatory cytokines such as TNF-α, IL1β, or INF-γ, which promote CCL5 production by keratinocytes. Thus, CCL5 production in psoriatic lesions may amplify the inflammation in the lesions (31). In atherosclerosis, macrophages are the major CCL5-expressing cells in the atherosclerotic plaque, CCL5 expression in macrophages is promoted by IFN-γ. CD8α⁺ dendritic cells aggravate atherosclerosis, likely by inducing Th1 cell response, which promotes CCL5 expression in macrophages and increased infiltration of leukocytes and lesion inflammation (32). BCL2A1 is a member of the BCL2 family. The process of apoptosis is controlled by proteins of the BCL2 family, Increased expression of BCL2A1 protein was associated with psoriatic epidermal hyperplasia (33). It’s also involved in vascular endothelial cell apoptosis and the formation of atherosclerotic plaque. Macrophage resistance to apoptosis was enhanced using macrophage-specific human BCL2 overexpression, have also shown accelerated early atherosclerotic plaque development (34). NCF2 gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein complex, which is known as nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome (35). As the main source of reactive oxygen species (ROS), the NADPH oxidase family plays an important role in various cellular functions such as antibacterial, anti-inflammatory, and redox signaling (36). ROS are messenger molecules that play a prominent role in cell metabolism-regulating cell proliferation, differentiation and death (37). In psoriasis, it has been reported that an increased intracellular ROS production and an enhanced NADPH oxidase activity in fibroblasts obtained from skin lesions of psoriatic patients (38). NADPH oxidase 4 expressed in dermal fibroblasts is essential for the redox paracrine regulation of epidermal keratinocytes proliferation (39). In atherosclerosis, oxidative stress is a risk factor for it. NADPH seems to mediate its detrimental effects by promoting inflammation in atherosclerosis (40). However, few studies directly analyze the role of NCF2 in psoriasis and atherosclerosis, which emphasizes its importance in future research.

Prior study explored the inflammatory and lipid genes related to atherosclerotic cardiovascular disease in skin and serum from patients with psoriasis (41). It found an increase in skin and serum gene expression for MCP-1 and MDC in psoriasis compared with healthy controls, and lipid metabolism (LXR-α, PPAR-α) genes decreased in psoriasis versus healthy controls (41). Our study also found that new genes like CSF2RB, IL1RN, CCL5, MMP9, CD53, NCF2 and TLR2 associated with Inflammation present high expression both in psoriasis and atherosclerosis. In addition, the lipopolysaccharide-mediated signaling pathway which was found involving many co-expressed genes would induce the release of MCP-1.

Mehta et al. used a bioinformatics approach of lesional psoriasis skin and atherosclerotic plaques, showed that IFN-γ and TNF-α are the dominant pro-inflammatory signals linking atherosclerosis and psoriasis, more importantly, both IFN-γ and TNF-α are increased in the serum of patients with moderate-to-severe psoriasis and their respective receptors in atherosclerotic plaques are increased. Stimulation of primary aortic endothelial cells and ex-vivo atherosclerotic tissue with IFN-γ and TNF-α synergistically increased monocyte and T-cell chemoattractants and adhesion molecules, concomitant with a decrease in endothelial barrier integrity. Their finding suggested IFN-γ/TNF-α synergy may provide a critical pro-inflammatory link between psoriatic skin inflammation and distant vessel atherosclerosis (42). Because of the strong genetic similarity between psoriasis and cardiovascular diseases (24), unlike previous studies, our research pays more attention to the exploration of hub genes and related TFs that are common to psoriasis and atherosclerosis. We have constructed a complex interaction network to identify the key nodes through their common DEGs. This comprehensive bioinformatics method has been proven to be reliable in a variety of diseases (43, 44). In addition, we also analyzed related TFs and verified their expression levels in the original data set. Our research will provide potential directions for the study of the molecular mechanism of psoriasis complicated by atherosclerosis.

Although previous studies have separately explored the hub genes associated with psoriasis (45) and atherosclerosis (46). However, few studies have explored the common molecular mechanism between them by advanced bioinformatics methods. Due to the high comorbidity rate between psoriasis and atherosclerosis, we explored and identified the common DEGs, hub genes and TFs between the two for the first time, which helped to further clarify the mechanism of psoriasis and atherosclerosis. However, our research also has some limitations. First of all, this is a retrospective study that requires external verification to verify our findings; Secondly, the function of the hub gene needs to be further verified in an in vitro model, which will be the focus of our future work.

In summary, we identified the common DEGs of psoriasis and atherosclerosis and performed enrichment and PPI network analysis. We found that psoriasis and atherosclerosis had many common pathogenic mechanisms, which may be mediated by specific hub genes. This study provides new insights for the further study of the molecular mechanism of psoriasis complicated with atherosclerosis.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

JJ and YS developed a major research plan. WS and YZ analyze data, draw charts and write manuscripts. XZ and YW helped collect data and references. All authors contributed to the article and approved the submitted version.

This work was supported by Suzhou Minsheng Technology - Medical and Health Application Foundation (SYS2020135) and 2020 Medical Research Project of Jiangsu Provincial Health Commission (Z2020017).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.