Advances In Immunological Research Related To Common Adipokines And Psoriasis

Psoriasis is a common chronic inflammatory skin disease, often associated with obesity, diabetes and other metabolic abnormalities. In recent years, people have gradually realized that obesity is also a chronic low-degree systemic inflammation, and a large number of adipokines and inflammation-related signal regulation play an important role in its occurrence and development. Compared with the general population, psoriasis patients with a higher incidence of obesity. This article reviews the possible immunological mechanisms of the interaction between psoriasis and common adipokines.
1. Leptin
Leptin is a regulator of appetite and energy consumption, mainly produced by fat cells in white adipose tissue. Studies have also shown that leptin can also be produced in non-adipose tissue such as gastric mucosa and placental trophoblast cells. It is known to play an important role in chronic inflammatory states such as obesity. Leptin levels in obese individuals and chronic inflammation, can't play to suppress appetite, reduce feeding, and other functions in the body, so some people think that the sensitivity of leptin in patients with lower or no response, the leptin resistance (leptin to hold), its mechanism has not been fully elucidated, studies have shown that the generation of leptin resistance may be related to leptin OB – the body related to the sudden change of R. In addition, proteins such as il-1ra and cytokine signaling inhibitory protein-3 (SOCS3) may negatively inhibit the function of leptin, thereby promoting the occurrence of leptin resistance. Hamminga et al. speculated that increased leptin levels in obese patients may promote psoriasis by releasing pre-inflammatory factors. Weight loss can significantly reduce leptin levels, improve insulin sensitivity, and reduce the possibility of metabolic syndrome and cardiovascular disease. Leptin and leptin receptor expression were significantly higher in patients with severe psoriasis than in controls. Leptin levels in peripheral blood of patients with psoriasis are increased not only from adipose tissue but also from inflammatory processes.
There are many subtypes of leptin receptors, among which the long-chain receptor subtype ob-rb has signal transduction function and is the main receptor that mediates the biological function of leptin. Leptin receptor is a member of the il-6 receptor family and has no enzyme activity. It mainly realizes signal transduction by activating tyrosine protein kinase 2 (JAK2). JAK2 binds to the receptor and activates SOCS3, which is
One of the negative feedback regulators of the tyrosine kinase/signal transductor and transcriptional activator (JAK/STAT) pathways. Soluble leptin receptor is the main binding protein of leptin in human blood, which is produced by hydrolysis and exocytosis of leptin receptor on cell surface, and can regulate the bioavailability of leptin. Leptin sensitivity varies with the concentration of soluble leptin receptors in the blood of metabolic diseases. Obesity, insulin resistance and type 2 diabetes are known to be negatively correlated with the level of soluble leptin receptors, but the level of soluble leptin receptors in psoriasis patients is not clear.
Leptin has been found to promote the proliferation, differentiation, migration and secretion of a large number of inflammatory factors in keratinocytes and promote the formation of blood vessels. When leptin was co-cultured with fibroblasts, it was found that proinflammatory factors such as interleukin-6 (il-6), chemokine -1(cxcl-1), monocyte chemokine protein-1 (McP-1), interleukin-8 (il-8), angiopoietin-1, and stromal cell-derived factor-1 (sdf-1) were significantly increased, and fibroblasts in psoriasis skin lesions secreted more cytoadhesion molecules (icam-1). In vitro experiments have confirmed that leptin promotes the differentiation of CD4+T cells into Th17 cells, which is achieved through leptin receptors, and leptin also promotes the secretion of il-17 by T cells. Leptin increases the expression of various activated markers, enhances phagocytosis and upregulates cytokine secretion in monocytes. In endothelial cells, leptin upregulates the expression of adhesion molecules and induces oxidative stress. Leptin plays a dual role in inflammation: on the one hand, it activates monocytes and macrophages and promotes the secretion of pro-inflammatory cytokines tnf-alpha, il-6 and il-9; on the other hand, it can guide T cells to differentiate into Th1. It shows that it can not only induce the secretion of inflammatory cytokines by different cells in the skin, but also can make the infiltrated immune cells adapt to the environment through the changes of surface molecules expressed, thus playing a pro-inflammatory role in the pathogenesis of psoriasis.
2. Adiponectin
Adiponectin, which is produced mainly by white adipose tissue, was previously thought to be a metabolic intermediate of insulin resistance, but now it is believed to be an intermediary of immune response. Adiponectin monomers can form oligomers by trimerisation of their collagen regions, but both trimerers and oligomers exist in peripheral blood, which may have different effects on insulin sensitivity. Activated immune cells release leucocyte elastase, which shears adiponectin. Different peptides may act differently after shearing. Adiponectin in the process of different diseases have different adjust action, such as in type 2 diabetes, metabolic syndrome and other metabolic diseases, the adiponectin level and TNF alpha and negatively correlated with the levels of IL – 6, prompt adiponectin in the process of positive energy balance have the effect of inhibiting inflammation, studies have shown that adiponectin may inhibit the activity of the nf-kappa B play its anti-inflammatory function suppression. On the contrary, in autoimmune diseases and chronic inflammatory diseases such as type I diabetes, rheumatoid arthritis and systemic lupus erythematosus, adiponectin can up-regulate the expression of il-6, McP-1 and other inflammatory factors, thus promoting inflammation. These findings suggest that adiponectin has a bidirectional regulatory effect. Adiponectin can activate AMPK, p38-mapk, c-jun amino-terminal kinase (JNK), and peroxisomal proliferators by binding to AdipoR1 and AdipoR2 receptors. Adiponectin, when combined with AdipoR1/AdipoR2, promotes the proliferation and migration of keratinocytes through the extracellular signal regulation kinase (ERK) signaling pathway. Jung MY etc., found that adiponectin can by phospholipase C – gamma gamma (PLC)/JNK/nf-kappa B signal transduction pathways, increase the dendritic cells MHC Ⅱ class molecular expression, make its maturity and activation and secretion of proinflammatory factor; Adiponectin ACTS on dendritic cells and promotes Th1 and Th17 cell responses both in vivo and in vitro. In classic microphones sinensis mott induced mouse model of psoriasis samples, adiponectin can act directly on the leather gamma delta T cells in mice, by adipoR1 inhibit synthesis of IL – 17, at the same time also confirmed with psoriasis skin tissue, especially the subcutaneous fat of adiponectin level is lower, for the adiponectin play a role in the pathogenesis of psoriasis provide evidence. Adiponectin can induce monocytes and macrophages to release anti-inflammatory cytokines il-10 and il-1 receptor antagonists, thereby inhibiting il-6 levels. Adiponectin can also inhibit the secretion and biological activity of tnf-alpha, which also inhibits the production of adiponectin. In endothelial cells, adiponectin, in contrast to tnf-alpha, down-regulates the expression of adhesion molecule icam-1 and vascular cell-adhesion molecule 1 (vcam-1). Taken together, the researchers concluded that adiponectin was beneficial.
3. Visfatin
Endolipids are mainly highly expressed in visceral tissues, and are positively correlated with abdominal obesity, fasting insulin and insulin resistance index, and negatively correlated with insulin sensitivity index and high-density lipoprotein. Endolipids can reduce plasma glucose and insulin levels, and have an insulin-like effect on insulin sensitivity. It was found that endolipids can bind to insulin receptors, activate insulin signaling pathways, and produce insulin-like activity that can rapidly reduce blood glucose and effectively prevent insulin resistance. Endolipids act on keratinocytes through nf-kappa B and STAT signaling pathways, promoting the expression of various inflammatory factors and promoting the development of psoriasis. Endoliptin ACTS on endothelial cells, significantly increasing the level of vascular endothelial growth factor (VEGF) secreted by endothelial cells and decreasing the expression of metalloproteinases (timp-1 and timp-2), resulting in endothelial hyperplasia and capillary cavity formation. These effects are achieved by activating PI3K/Akt and erk1/2 pathways. Bae YH et al. found that endothelin can induce endothelial cells to secrete fibroblast growth factor 2(FGF-2), which is dependent on Notch1 signaling pathway. In a collagen-induced arthritis mouse model, endolipid knockout monocytes inhibit disease progression by reducing il-6 secretion, CD4+T cell differentiation to Th17 cells, and monocytes/macrophages and neutrophils infiltration in the joint.
4. Chemerin
Chemokines are adipokines associated with obesity, insulin resistance, metabolic syndrome and inflammation and play an important role in the development of tumors in many organs. Visceral adipose tissue is one of the main sources of chemokines, which are inflammatory cytokines released by white adipose tissue. The concentration of chemokines in the blood is often strongly correlated with body mass index (BMI). Chemokines have three receptors, chemR23(also known as CMKLR1), CCRL2 and GPR1. CCRL2 can enrich chemokines on the cell surface and mediate the cells to present chemR23 with chemokines. ChemR23 and GPR1 can cause chemokine related signal transmission through the Ras homologous gene (Rho)/rho-related helicokinase (Rho A/ ROCK) pathway, but the specific role of GPR1 is still not completely clear. Chemokines play an important role in both natural immunity and acquired immunity. On the one hand, chemokines can regulate antigen-presenting cells (such as dendritic cells, macrophages and natural killer cells) in the range of nanomolar concentration and recruit them into inflammatory regions. On the other hand, it can prevent the synthesis of pro-inflammatory mediators, which act on macrophages in an anti-inflammatory manner. Epidermis is rich in chemokines, which play an important role in skin inflammation. Studies have shown that the expression of chemokines in psoriasis increases, and the infiltration of dendritic cells expressing chemR23 increases, and the chemokinine /chemR23 axe-mediated immune effect plays a role in the early development of psoriasis. In cultured human skin, il-17 and il-22, key cytokines of psoriasis, were found to significantly reduce the expression of chemokines. In arthritis, chemokines act on chondrocytes by activating MAPKs (ERK 1/2) and Akt signaling pathways, producing a large number of inflammatory factors such as il-6, il-8, tnf-alpha, il-1 beta, and a variety of matrix metalloproteinases. Pro-inflammatory factors such as tnf-alpha, il-1 beta, and il-6 regulate chemR23 expression on the surface of human endothelial cells. In addition, chemokines can also induce neovascularization by activating MAPK, Akt, and endothelial gelatinase (mmp-2/9) and other related signaling pathways, and promote endothelial cell proliferation, migration, and capillary lumen formation.
5. Retinol-binding protein 4(RBP4)
RBP4 is a new adipokine discovered in 2005. Serum RBP4 is mainly secreted by the liver, followed by adipose tissue. In vivo, RBP4 is mainly responsible for the transport of retinol, followed by the binding of thyroid hormone transport protein (TTR) to increase the stability of rbp4-retinol. Blood RBP4 level was increased in patients with psoriasis and was positively correlated with PASI score, which may be one of the mediators related to the tendency of psoriasis combined with metabolic syndrome.
RBP4 is also secreted by macrophages in adipose tissue. Broch M et al. detected the expression level of RBP4 in monocytes in peripheral blood and macrophages at different stages. After inflammation stimulated by tnf-alpha or LPS, the expression of RBP4 in macrophages decreased significantly, indicating that macrophages in adipose tissue were not the main source of increased RBP4 in psoriasis. RBP4 wed STRA6 membrane receptor, activation through NADPH oxidase and nf-kappa B, can stimulate the endothelial cells expressing vascular cell adhesion factor (VCAM 1) and intercellular adhesion factor (ICAM – 1), choice of E element, monocyte chemotactic protein 1 (MCP 1) and inflammatory factor such as IL – 6, these factors mainly adjust the leukocyte recruitment and endothelium adhesion, in the process of endothelial tissue inflammation plays an important role.
To sum up, cytokines related to psoriasis, such as tnf-alpha, il-17, il-22 and il-6, can act on the metabolic process of fat cells and affect fat formation and insulin resistance. Adipokines secreted by adipocytes, such as leptin, endolipid, chemokines and retinol-binding protein 4, can promote the production of inflammatory factors through Th17 and Th1 cells. Adiponectin may play an anti-inflammatory role in this process and control inflammation, thus forming an interaction network that regulates the balance of inflammatory response. The imbalance between immune cells and fat cells may be one of the important factors in the pathogenesis and development of psoriasis, but the exact mechanism of its action still needs to be further studied. In-depth study on the role and mechanism of adipokines may provide new basis for the diagnosis, molecular identification and therapeutic target discovery of psoriasis.