T lymphocyte subsets are derived from lymphoid stem cells of bone marrow, which differentiate and mature into T cell subsets that recognize various antigens under the induction of thymus. They are distributed to immune tissues and organs of the whole body through lymphatic circulation and blood circulation, exerting cellular immunity and immune regulation functions. Early evidence suggests that both AS and psoriasis are th1-mediated diseases (26). The Th1 subtype is the most studied cell type in psoriasis at present, but the role of other T cell subtypes in different stages of psoriasis and atherosclerosis should not be ignored (27). Recent studies have found that Th17, CD8+T cells and γδT cells can produce IL-17 and participate in the pathogenesis of psoriasis and atherosclerosis (1).

Th1 is the key to the beginning of the inflammatory cascade in psoriasis (28) and activates keratinocytes through activation of neutrophils, macrophages and CD8+ cytotoxic T lymphocytes (29). The main mediators of Th1 activity are IFN-γ and IL-2, which act on keratinocytes and induce the production of antimicrobial peptides, leading to an inflammatory cascade. Elevated Th1 cells in patients with unstable angina and acute coronary syndrome (ACS) suggest that Th1 cells also play a key role in atherosclerosis, which is thought to be driven primarily by the cytokine IFN-γ that is the hallmark of the Th1 response. Therefore, the common feature between psoriasis and AS is that IL-12 stimulates the activation of Th1 response, which in turn activates the corresponding immune cells to produce an inflammatory cascade that affects subsequent endothelial dysfunction (17). In addition to the classic Th1 and Th2 cytokines, recently discovered members of the IL-17 cytokine family play important roles in regulating cellular and humoral immune responses.

Th17 cells in psoriasis process release different cytokines such as IL-17, IL-22 and tumor necrosis factor -α (30) and participate in the process of macrophage stimulation of dendritic cells (DC) to spread inflammatory response. Increased the release of inflammatory mediators such as monocyte chemotactic protein (McP-1), nitric oxide and vascular endothelial growth factor, suggesting that Th17 plays a positive role in promoting the inflammatory response in psoriasis. Compared with patients with stable ACS, Th17 cells and IL-17 levels were increased in patients with ACS (17, 31). Christian Erbel et al. established AS mice with high fat diet, and inhibition of IL-17A significantly reduced the atherosclerotic lesion area (P < 0.001), maximum stenosis (P < 0.001) and lesion vulnerability. Mice treated with IL-17A mab had reduced cell infiltration, down-regulated activation markers (e.g. Vcam-1) on endothelial cells and immune cells, and reduced cytokine/chemokine secretion (e.g. IL6, TNF-α, CCL5). It is suggested that IL-17A plays a role in AS through its extensive pro-inflammatory and pro-apoptotic effects (32, 33). However, there are different conclusions about the role of Th17 cells in AS (34). Onno J de Boer et al. (35) found that IL-17A/F(+) neutrophils were more common in complex plaques than in intact plaques. No IL-17A/F(+) T cells (TH17) were observed. Il-17e is expressed in normal and atherosclerotic smooth muscle cells and endothelial cells, and is also widely expressed in mature B cells in advanced plaques. Both cultured smooth muscle cells and endothelial cells expressed IL-17E and its functional receptor (IL-17Rb). Suggesting that the additional presence of IL-17E(+) B cells and IL-17A/F(+) neutrophils in advanced and complex plaques suggests that the complex contribution of IL-17 family cytokines to human atherosclerosis may depend on the stage and activity of the disease. In summary, further studies are needed to prove whether Th17 can promote atherosclerosis.

In addition, regulatory T cells (Treg) have also been found to be associated with psoriasis and AS. Treg is a subset of T lymphocytes, whose main function is to inhibit the activation and proliferation of T cells through mechanisms driven by cell-contact-dependent and cell-contact-independent anti-inflammatory cytokines (36). The inhibitory function of Treg was significantly impaired in patients with psoriasis, leading to chronic auto-inflammation in patients with psoriasis. The level of Treg in patients with cardiovascular disease is reduced (5), and the reduction in the number of Treg cells or their reaction ability can lead to the progression of atherosclerosis (37). It can be seen that the inflammatory process of psoriasis and atherosclerosis has a certain correlation with the decrease of Treg level.

Macrophages are involved in host defense, dynamic homeostasis, and tissue repair. They can be divided into monocytes or tissue-derived macrophages according to the development degree (38), which play a key role in the pathogenesis of various immune-mediated diseases and chronic inflammation (39). Macrophages have traditionally been divided into pro-inflammatory M1 subtypes and anti-inflammatory M2 subtypes. Macrophages have strong heterogeneity and can be adjusted to adapt to the surrounding environment according to the pathological state (40–42). Macrophages are closely related to the development of psoriasis - atherosclerosis comorbidities.

Psoriasis is an immune-mediated inflammatory disease in which inflammatory cells promote the development of psoriatic lesions and atherosclerotic plaques. In psoriasis, macrophages acquire a pro-inflammatory phenotype and produce cytokines such as IL-23, TNF-α, and IL-1β. Il-23 and IL-1β activate T cells to produce cytokines such as IL-17 and IFN-γ that promote further polarization of macrophages, resulting in a sustained inflammatory state (38, 43). TNF-α can induce the expression of endothelial cell adhesion molecules that can promote the adhesion between monocytes and endothelial cells, and thus promote AS (44). In addition, injured endothelial cells can also secrete vascular endothelial growth factor (VEGF), which promotes the formation of vascular plaque by stimulating the aggregation of macrophages in arterial endothelial cells (18). Superoxide dismutase 2 (SOD2) is essential in the regulation of macrophage function and anti-oxidative stress (45), which helps to alleviate the damage of reactive oxygen species (ROS) to cells. Yvonne et al. found in psoriatic mice that the expression of SOD2 in macrophages was reduced by 60%, which may lead to enhanced oxidative stress in cells, aggravate cell damage and promote the formation of atherosclerotic plaques (45). In addition, macrophages in patients with psoriasis secrete increased Microparticles (MPs), which promote systemic inflammatory response and coagulation disorders, which may affect the thickness of intima and middle layer and the curvature of capillaries in nail folds, thus promoting the progression of atherosclerosis (46, 47). In conclusion, macrophages promote and maintain inflammatory response and promote the development of AS in patients with psoriasis. In addition, macrophages not only promote the expression of inflammatory factors in patients with psoriasis, but also increase the formation of cholesterol crystals and lipid uptake, affect cholesterol excretion, and further promote the occurrence of AS (45, 48, 49).

In conclusion, macrophages are involved in the disease process of psoriasis and AS and play a crucial role, but further studies are still needed to clarify their mechanisms.

The role of neutrophils in atherosclerosis and psoriasis has also been gradually recognized. Animal models and clinical trials have proved that their common mechanism of action is that neutrophils drive excessive proliferation of keratinocytes through IL-17, leading to chronic skin inflammation (17). Neutrophils act as important defenders in acute inflammatory responses, eliminating foreign pathogens by releasing reactive oxygen species and proteolytic enzymes that may also lead to tissue destruction. In addition, neutrophils have a variety of biological functions in innate immunity, and neutrophils can synthesize and release cytokines, chemokines and growth factors after stimulation (50). When these factors interact with damaged endothelial cells, neutrophils release granular proteins that increase leukocyte recruitment in the endothelial layer and ultimately promote inflammation and foam cell development, leading to further development of atherosclerosis and psoriatic inflammation (51).

Psoriasis increases neutrophil activation and the release of neutrophil associated proteins, such as calcium-binding proteins (S100A8/A9), which may further provide a link between psoriasis and cardiometabolic disease. S100A8/A9 is released by activated neutrophils and upregulated in psoriatic lesions (50). Studies (50) have proved that S100A8/A9 is closely related to the severity of skin diseases and vascular inflammation (VI). In conclusion, neutrophils and their proteins may be involved in the early atherosclerotic environment of psoriasis and independently predict endothelial dysfunction. With the development of various studies, a new subtype of neutrophil – low density granulocyte (LDG) is becoming a hot research direction in the pathophysiology of psoriasis and cardiovascular diseases. LDG is characterized by high pro-inflammatory activity, changes in phagocytosis, mediated production of type I interferon, and high abundance in atherosclerotic plaques and plasma in patients with psoriasis (50). LDG differs from autologous normal density granulocytes (NDG) and healthy control neutrophils (52, 53) in gene expression level, and LDG is also different from NDG in phenotype. Among these differences, the most striking was their increased ability to spontaneously form neutrophil extracellular traps (NETs). This new subtype of neutrophil will provide more direct evidence of the link between psoriasis and cardiometabolic disease.

The inflammatory microenvironment of psoriatic lesions and early atherosclerotic plaques, including chemokines and cytokines secreted by dendritic cells and NK cells in immune cells like immune cells, can promote the inflammatory environment and lead to the formation of psoriatic plaques or atherosclerotic plaques.

Dendritic cells (DC) not only serve as antigen presenting agents and cellular gene producers, but also as Bridges between innate and adaptive immune systems, and play an important role in continuing chronic inflammation-induced cascades (54). For example, plasmacytoid dendritic cells (pDCs) are involved in type 1 interferon (IFN) response (28, 55), while dendritic cells (mDCs) from bone marrow are key cells in the production of IL-12 and IL-23, thus inducing the expansion of specific Th cells. These two DCS play an important role in the formation of psoriatic inflammation. Although new evidence suggests that DC also plays a role in atherosclerotic plaque formation and regulates atherosclerotic plaque vulnerability through cholesterol metabolism and adaptive immune responses (56), the joint role of DC in psoriasis and atherosclerosis needs further study.

NK cells are generally considered to belong to the lymphocytes of the innate immune system and can directly kill viruses/cancer cells, while also producing cytokines including IFN-γ and TGF-β. Ottaviani et al. (57) found that 5-8% of inflammatory infiltrating cells entering psoriatic skin were composed of CD56+ and CD3− cells in the NK cell phenotype, most of which were CD56bright subsets of NK cells. Compared to CD56dim NK cells, CD56bright cells are considered to represent more immature cells with less cytotoxicity, while simultaneously activating the antigen CD69 and producing large amounts of IFN-γ in vitro. IFN-γ is an important mediator of inflammation in psoriasis and atherosclerosis, stimulating the expression of MHC-II molecules and ICAM-1. Elevated serum IFN-γ in patients with psoriasis may stimulate the proliferation of keratinocytes, resulting in keratinization defects and changes in the biological characteristics of keratinocytes, resulting in typical psoriatic lesions (58). In addition, IFN-γ enhances antigen presentation, activates T lymphocytes, interacts with a variety of inflammatory factors, promotes inflammatory response at the atheroma site, and aggravates the progression of the disease. Therefore, cytokines produced by NK cells play an important role in inflammatory changes in psoriasis and atherosclerosis.

In conclusion, T cells, macrophages and neutrophils participate in the pathogenesis of psoriasis and AS, and play an important role in different stages of psoriasis and AS.