Li Jiaqi, Chang Wenjuan, Li Junqin, Zhao Xiya, Li Xinhua
School of Public Health, Shanxi Medical University, Taiyuan, China.
Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China.
Arch Dermatol Res. 2025 Jan 10;317(1):227. doi: 10.1007/s00403-024-03668-9.
Psoriasis is an inflammatory dermatosis that features overproliferation and inflammatory reaction of keratinocytes. A study reported that IL-22 is involved in the pathogenesis of psoriasis by mediating miR-124 to regulate the expression of fibroblast growth factor receptor 2 in keratinocytes. A microRNA may target multiple target genes. Therefore, we speculate that miR-124-3p may also target other downstream genes to affect IL -22-induced keratinocyte function. A possible target gene of miR-124-3p, growth factor receptor-bound protein 2 (GRB2), was screened by analyzing the target gene databases. GRB2 expression was elevated and miR-124-3p expression was decreased in psoriatic lesions compared to psoriatic adjacent normal skins and healthy controls. We performed the following cell experiments in the IL-22-stimulated HaCaT cell model. In keratinocytes transfected with the miR-124-3p mimics, GRB2 expression was significantly lower. We analyzed the regulation of keratinocyte proliferation by GRB2 and miR-124-3p. High levels of GRB2 promoted keratinocyte proliferation and expression of Ki67, PCNA, and K16, which were inhibited by low expression of GRB2. In addition, we found that the effect of GRB2 inhibitors on the proliferation and inflammatory response of keratinocytes was dose-dependent. Finally, we investigated the influence of GRB2 on inflammatory mediators in keratinocytes with the ELISA. After low expression of GRB2, the mRNA expression and secretion of the pro-inflammatory factor were suppressed. When both GRB2 and miR-124-3p were overexpressed, the cellular overproliferation and inflammation caused by GRB2 overexpression were significantly reversed by miR-124-3p. In summary, IL-22-mediated miR-124-3p regulates keratinocyte hyperproliferation and inflammatory response by suppressing GRB2 expression in psoriasis.
银屑病是一种以角质形成细胞过度增殖和炎症反应为特征的炎症性皮肤病。一项研究报道，白细胞介素-22（IL-22）通过介导微小RNA-124（miR-124）调节角质形成细胞中成纤维细胞生长因子受体2的表达，从而参与银屑病的发病机制。一种微小RNA可能靶向多个靶基因。因此，我们推测miR-124-3p也可能靶向其他下游基因，以影响IL-22诱导的角质形成细胞功能。通过分析靶基因数据库，筛选出miR-124-3p的一个可能靶基因，即生长因子受体结合蛋白2（GRB2）。与银屑病相邻正常皮肤和健康对照相比，银屑病皮损中GRB2表达升高，而miR-124-3p表达降低。我们在IL-22刺激的HaCaT细胞模型中进行了以下细胞实验。在转染了miR-124-3p模拟物的角质形成细胞中，GRB2表达显著降低。我们分析了GRB2和miR-124-3p对角质形成细胞增殖的调节作用。高水平的GRB2促进角质形成细胞增殖以及Ki67、增殖细胞核抗原（PCNA）和角蛋白16（K16）的表达，而GRB2低表达则抑制这些作用。此外，我们发现GRB2抑制剂对角质形成细胞增殖和炎症反应的影响呈剂量依赖性。最后，我们用酶联免疫吸附测定法（ELISA）研究了GRB2对角质形成细胞中炎症介质的影响。GRB2低表达后，促炎因子的信使核糖核酸（mRNA）表达和分泌受到抑制。当GRB2和miR-124-3p均过表达时，miR-124-3p可显著逆转GRB2过表达引起的细胞过度增殖和炎症。综上所述，在银屑病中，IL-22介导的miR-124-3p通过抑制GRB2表达来调节角质形成细胞的过度增殖和炎症反应。
