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miR-155 通过 IRF2BP2/KLF2/NF-κB 通路促进银屑病 HaCaT 细胞的炎症反应。

miR‑155 promotes an inflammatory response in HaCaT cells via the IRF2BP2/KLF2/NF‑κB pathway in psoriasis.

机构信息

Department of Immunology, School of Medicine, Jianghan University, Wuhan, Hubei 430056, P.R. China.

Department of Pathogenic Biology, Medical College, Wuhan University of Science and Technology, Wuhan, Hubei 430065, P.R. China.

出版信息

Int J Mol Med. 2024 Nov;54(5). doi: 10.3892/ijmm.2024.5415. Epub 2024 Sep 2.

Abstract

Psoriasis is a chronic inflammatory skin condition with numerous causes, including genetic, immunological and infectious factors. The course of psoriasis is long and recurrence is common; pathogenesis is not completely understood. However, there is an association between advancement of psoriasis and aberrant microRNA (miR or miRNA)‑155 expression. Through bioinformatics, the present study aimed to analyze the differentially expressed genes and miRNAs in psoriasis and its biological mechanism and function psoriatic inflammation. First of all, differentially expressed genes (DEGs) and miRNAs (DEMs) in patients with psoriasis were identified using GEO2R interactive web application. A psoriasis inflammatory model was established using lipopolysaccharide (LPS)‑treated HaCaT keratinocytes, which were transfected with miR‑155 mimic or inhibitor. Cell Counting Kit‑8 was used for the assessment of cell viability and proliferation, and changes in the cell cycle were examined using flow cytometry. ELISA and reverse transcription‑quantitative PCR (RT‑qPCR) were used to detect the expression levels of the inflammatory factors IL‑1β and IL‑6. The dual‑luciferase reporter assay was used to verify the targeting association between miR‑155‑5p and IFN regulatory factor 2 binding protein 2 (IRF2BP2). To verify the targeting association of miR‑155 and the IRF2BP2/kruppel‑like factor 2 (KLF2)/NF‑κB signaling pathway, expression levels of IRF2BP2, KLF2 and p65 were identified by RT‑qPCR and western blotting. IRF2BP2 levels were also confirmed by immunofluorescence, in conjunction with bioinformatics database analysis. Overexpression of miR‑155 inhibited proliferation of HaCaT cells and increased the number of cells in S phase and decreasing number of cells in G1 and G2 phase. In the LPS‑induced inflammatory state, miR‑155 overexpression heightened the inflammatory response of HaCaT cells while inhibition of miR‑155 lessened it. Suppression of inflammatory cytokine expression by miR‑155‑5p inhibitor was reversed by knockdown of IRF2BP2. miR‑155 was shown to interact with IRF2BP2 to negatively regulate its expression, leading to decreased KLF2 expression and increased p65 expression and secretion of inflammatory factors, intensifying the inflammatory response of HaCaT cells. Therefore, miR‑155 may contribute to development of psoriasis by inducing tissue and cell damage by increasing the inflammatory response of HaCaT cells via the IRF2BP2/KLF2/NF‑κB pathway. In conclusion, the results of the present study offer novel perspectives on the role of miR‑155 in the onset and progression of psoriasis.

摘要

银屑病是一种慢性炎症性皮肤病,其病因众多,包括遗传、免疫和感染因素。银屑病的病程长且容易复发,其发病机制尚不完全清楚。然而,银屑病的发展与异常的 microRNA(miR 或 miRNA)-155 表达之间存在关联。本研究通过生物信息学分析,旨在探讨银屑病及其生物学机制和功能中差异表达基因和 miRNA(DEGs 和 DEMs)。首先,使用 GEO2R 交互式网络应用程序鉴定银屑病患者中的差异表达基因(DEGs)和 miRNAs(DEMs)。使用脂多糖(LPS)处理的 HaCaT 角质形成细胞建立银屑病炎症模型,并用 miR-155 模拟物或抑制剂转染。用细胞计数试剂盒-8 评估细胞活力和增殖,用流式细胞术检测细胞周期变化。酶联免疫吸附试验和逆转录-定量聚合酶链反应(RT-qPCR)用于检测炎症因子白细胞介素-1β(IL-1β)和白细胞介素-6(IL-6)的表达水平。双荧光素酶报告基因实验验证 miR-155-5p 与干扰素调节因子 2 结合蛋白 2(IRF2BP2)之间的靶向关联。为了验证 miR-155 与 IRF2BP2/ 核因子-κB 信号通路的靶向关联,通过 RT-qPCR 和 Western blot 检测 IRF2BP2、Kruppel 样因子 2(KLF2)和 p65 的表达水平。还通过免疫荧光与生物信息学数据库分析共同验证了 IRF2BP2 的表达水平。miR-155 的过表达抑制了 HaCaT 细胞的增殖,增加了 S 期细胞数量,减少了 G1 和 G2 期细胞数量。在 LPS 诱导的炎症状态下,miR-155 的过表达增强了 HaCaT 细胞的炎症反应,而 miR-155 的抑制则减弱了炎症反应。miR-155-5p 抑制剂对炎症细胞因子表达的抑制作用被 IRF2BP2 的敲低所逆转。结果表明,miR-155 通过与 IRF2BP2 相互作用负调控其表达,导致 KLF2 表达降低,p65 表达和炎症因子分泌增加,从而加剧 HaCaT 细胞的炎症反应。因此,miR-155 可能通过增加 HaCaT 细胞的炎症反应,诱导组织和细胞损伤,从而导致银屑病的发生和发展。综上所述,本研究结果为 miR-155 在银屑病发病和进展中的作用提供了新的视角。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/abf8/11374146/df7b38d0a3ec/ijmm-54-05-05415-g00.jpg

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