microRNA-125a-5p 通过靶向 ETS-1/STAT3 调节调节性 T 细胞对 Th1 和 Th17 的作用在银屑病中。
MicroRNA-125a-5p regulates the effect of Tregs on Th1 and Th17 through targeting ETS-1/STAT3 in psoriasis.
机构信息
Department of Dermatology, Huashan Hospital, Shanghai Institute of Dermatology, Fudan University, Shanghai, 200040, China.
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
出版信息
J Transl Med. 2023 Sep 29;21(1):678. doi: 10.1186/s12967-023-04427-6.
BACKGROUND
Psoriasis is an inflammatory disease mediated by helper T (Th)17 and Th1 cells. MicroRNA-125a (miR-125a) is reduced in the lesional skin of psoriatic patients. However, the mechanism by which miR-125a participates in psoriasis remains unclear.
METHODS
The levels of miR-125a-5p and its downstream targets (ETS-1, IFN-γ, and STAT3) were detected in CD4 T cells of healthy controls and psoriatic patients by quantitative real-time PCR (qRT-PCR). In vitro, transfection of miR-125a-5p mimics was used to analyze the effect of miR-125a-5p on the differentiation of Th17 cells by flow cytometry. Imiquimod (IMQ)-induced mouse model was used to evaluate the role of upregulating miR-125a-5p by intradermal injection of agomir-125a-5p in vivo.
RESULTS
miR-125a-5p was downregulated in peripheral blood CD4 T cells of psoriatic patients, which was positively associated with the proportion of regulatory T cells (Tregs) and negatively correlated with the Psoriasis Area and Severity Index (PASI) score. Moreover, the miR-125a-5p mimics promoted the differentiation of Tregs and downregulated the messenger RNA (mRNA) levels of ETS-1, IFN-γ, and STAT3 in murine CD4 T cells. Furthermore, agomir-125a-5p alleviated psoriasis-like inflammation in an IMQ-induced mouse model by downregulating the proportion of Th17 cells.
CONCLUSIONS
miR-125a-5p may have therapeutic potential in psoriasis by restoring the suppressive function of Tregs on Th17 cells through targeting STAT3, and on Th1 cells indirectly through targeting ETS-1 and IFN-γ.
背景
银屑病是一种由辅助性 T（Th）17 和 Th1 细胞介导的炎症性疾病。在银屑病患者的皮损皮肤中，miR-125a（miR-125a）的水平降低。然而，miR-125a 参与银屑病的机制尚不清楚。
方法
通过实时定量 PCR（qRT-PCR）检测健康对照者和银屑病患者 CD4 T 细胞中 miR-125a-5p 及其下游靶标（ETS-1、IFN-γ和 STAT3）的水平。体外，通过转染 miR-125a-5p 模拟物，利用流式细胞术分析 miR-125a-5p 对 Th17 细胞分化的影响。采用咪喹莫特（IMQ）诱导的小鼠模型，评估皮内注射 agomir-125a-5p 上调 miR-125a-5p 在体内的作用。
结果
银屑病患者外周血 CD4 T 细胞中 miR-125a-5p 下调，与调节性 T 细胞（Tregs）的比例呈正相关，与银屑病面积和严重程度指数（PASI）评分呈负相关。此外，miR-125a-5p 模拟物促进 Tregs 的分化，并下调鼠 CD4 T 细胞中 ETS-1、IFN-γ和 STAT3 的信使 RNA（mRNA）水平。此外，agomir-125a-5p 通过下调 Th17 细胞的比例缓解了 IMQ 诱导的小鼠模型中的银屑病样炎症。
结论
miR-125a-5p 可能通过靶向 STAT3 恢复 Tregs 对 Th17 细胞的抑制功能，通过靶向 ETS-1 和 IFN-γ 间接恢复 Tregs 对 Th1 细胞的抑制功能，从而在银屑病中具有治疗潜力。
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