Studies show that psoriasis is a chronic inflammatory skin disease. Infiltration of immune cells in the skin and excessive proliferation of keratinocytes were the main pathological manifestations. A series of basic and clinical studies in psoriasis have shown that psoriasis is mediated by components of the innate and adaptive immune system, and there is significant immune infiltration in tissues. In the course of PSO, immune cells release a variety of inflammatory mediators, which act on keratinocytes and magnifies skin inflammation.Therefore, immune cells and inflammatory factors are the focus of research. At present, many effective biological agents are used to reduce inflammatory factors in patients to alleviate symptoms, such as tumor necrosis factor inhibitors, IL-17A antagonists, IL12-IL23 antagonists, etc.[13, 14, 15].In this study, bioinformatics methods and Bioconductor package in R language were used to analyze the expression matrix of psoriasis tissues with inflammation involvement, normal skin and normal skin tissue of psoriasis patients without inflammation involvement, and to summarize the degree of immune infiltration in psoriasis patients' skin lesions. The infiltration degree of 23 immune cells was significantly different from that of normal tissues, which confirmed that the abnormal infiltration of immune cells plays an indispensable role in the pathogenesis and progression of psoriasis, and further explained the relationship between immune micro-environment and psoriasis. The intersection of marker genes of immune cells and DEGs was used to obtain immune-related genes in psoriasis tissues. Four key genes, PRC1, GATA3, IL1RN and CCL20, were screened out through PPI network subcluster analysis. These four genes were significantly correlated with multiple immune cells and were related to psoriasis. PRC1 has been shown to be a substrate for a variety of cyclin-dependent kinases (CDK), which are present at high levels during the S and G2 / M phases of mitosis and exist in the nucleus during interphase. Finally, it accumulates in the intermediate region of the spindle in the mitotic postponement at the later stage. Previous experiments have confirmed that PRC1 is over-expressed in a variety of cancers, such as breast cancer, gastric cancer, liver cancer, non-small cell lung cancer, etc., and is associated with various invasive clinical pathological features and poor prognosis[18, 19]. PRC1 expression can be regulated and elevated through a variety of signaling pathways, such as non-estrogen receptor (ER), p53 and Wnt signaling pathways, which are frequently altered or mutated in several cancers[20–22].
In simple terms, PRC1 is associated with cell proliferation and is a marker gene for CD4+T cells. Accordingly, in psoriasis, keratinocytes proliferate excessively, the cell cycle is accelerated, and CD4+T cells infiltrate. Our experimental results showed that PRC1 was significantly correlated with Activated CD4+T cell and Type 2 T Helper cell in psoriasis. The relationship between Activated CD4+T cell and Activated CD4+T cell was significantly positive. We also found that PRC1 has high diagnostic value for psoriasis, but has no special performance in the treatment effect of biological agents. Immunohistochemical results also confirmed that PRC1 was significantly elevated in psoriatic tissues.
GATA3 has been shown to be critical for the proliferation and differentiation of human and mouse keratinocytes, regulating the expression of a variety of proliferation and differentiation markers, including Ki67 and filaggrin (FLG). Studies have shown that GATA3, the main regulator of T helper cells subgroup, may be a potential therapeutic target in the treatment of cancer, metabolic diseases, inflammation, tissue regeneration and repair. GATA3 determines the fate of plastic Treg by controlling whether it will convert in to either th1-treg or APC-T-reg. Wudh et al. interpret that Psori-CM02 impairs IMQ-induced psoriasis by promoting Th2 cell response targeting of GATA3.
IL1RN encodes a protein that binds to the IL-1 receptor and inhibits the binding of IL-1α and IL-1β, the first member of the IL-1 family to be described as having antagonistic functions. IL1RN is a susceptibility gene for psoriasis. In patients with psoriasis, the expression of CXCL2 and IL1RN in Treg cells and the expression of CCL3 in Treg and T helper cells were increased, while the NFKB1 binding modens in the enriched regions of psoriasis were accessible. SU et al. found that IL1RN is highly expressed in both psoriasis and atherosclerosis, and is related to inflammation.
CCL20 is the only known high affinity homologue of CCR6. In various subpopulations of CD4+T cells, CCR6 is highly expressed on Treg and Th17 cells and drives these cells to migrate to CCl20-rich inflammatory tissues. In addition, CCL20 inhibits Treg differentiation and promotes the pathogenic Th17 cells in intestinal associated lymphoid tissue galt, and high concentrations of CCL20 promote the pathogenic phenotype of CD4+T cells under inflammatory conditions. CD4+T cells expressing CCL20 and CCR6 are abundant in psoriatic lesions, and the serum level of CCL20 in patients with psoriasis is elevated. The TNF -α inhibitor infliximab significantly reduces local induction of CCL20 and shows great promise in psoriasis. Getschman et al. invented a group of CCL20 variants that competitively bind CCR6 with CCL20 to prevent psoriatic inflammation and up-regulation of IL-17A and IL-22.
Taken together, these four genes play an important role in immunizing inflammatory diseases. We tested the diagnostic value of these four genes by using the subject curve, and all of them have strong diagnostic significance. As we already know, GATA3 and CCL20 are highly expressed in psoriasis, while PRC1 has not been reported in the literature, but it also has strong diagnostic value. However, IL1RN is controversial. Some previous studies believed that IL1RN is an anti-inflammatory factor and its expression is reduced in psoriasis. However, in this study, we analyzed several data sets and immunohistochemical results of tissues, which showed that IL1RN expression was increased in psoriatic tissues. In addition to their diagnostic value, we analyzed the specificity of these four genes in treatment. Using several data sets, we analyzed three clinically common biological agent, tumor necrosis factor alpha inhibitors, IL-17A antagonists, and IL-12/23 inhibitors. The metrics we selected showed significant differences between pre-treatment and post-treatment. It is worth noting that the data results of non-response to Ustekinumab and Etanercept showed that the expression of GATA3 and IL1RN was not significant. In the treatment of psoriasis, patients are not sensitive to the selection of biological agents, which wastes the treatment time and cost.
Based on our experimental results, GATA3 and IL1RN may be associated with non-response to treatment. GATA3 expression of type 17 T Helper cell and activated dendritic cell showed negative correlation. The expression of IL1RN was positively correlated with neutrophil, type 1 T helper cell, and type 17 T helper cell. From the perspective of related immune cells, these immune cells do play an important role in the pathogenesis of psoriasis. So, what is the mechanism that influences the therapeutic effect in the non-response to treatment is still unknown. Our results can only prove that GATA3 and IL1RN have high specificity in non-response and can be used as indicators of therapeutic effect, but a large number of experimental data are still needed to support.